Comparison of pregnancy outcomes between GnRH antagonist protocol with freeze-all strategy and long-acting GnRH agonist protocol in women with adenomyosis undergoing IVF/ICSI: a propensity-score matching analysis

Background: Plenty of studies explored the most optimal treatment protocol for infertile women with adenomyosis in in-vitro fertilization (IVF) /intracytoplasmic sperm injection (ICSI), however, there is still no consensus on which treat- ment protocol is ideal for these women at present. So, we conducted this study comparing the pregnancy outcomes in infertile women with ultrasound-diagnosed adenomyosis who underwent GnRH antagonist protocol with freeze- all strategy or long-acting GnRH agonist protocol.

This was a retrospective cohort study and a propensity-score matching (PSM) analysis including 282 women diagnosed with adenomyosis undergoing their first IVF/ICSI cycle from January 2016 to July 2021 at the Assisted Reproduction Center, Northwest Women’s and Children’s Hospital, China. The patients were divided into two groups: the GnRH antagonist protocol with freeze-all strategy (n = 168) and the long-acting GnRH agonist protocol with fresh embryo transfer (n = 114) according their treatment protocols. The primary outcome was live birth rate. Cumulative live birth rate was also calculated.

After adjusting for confounders, clinical pregnancy rate (49.40% vs 64.04%; odds ratio (OR) 1.33; 95% con- fidence interval (CI) 0.70 to 2.37; P = 0.358), live birth rate (36.90% vs 45.61%; OR 1.10; 95% CI 0.61 to 2.00, P = 0.753) and cumulative live birth rate (51.79% vs 64.04%; OR 1.01; 95% CI 0.49 to 1.74, P = 0.796) were not significantly differ- ent between the GnRH antagonist protocol with freeze-all strategy and long-acting GnRH agonist protocol. Similar

were conducted in PSM analysis with clinical pregnancy rate (46.48% vs 60.56%; OR 1.33; 95% CI 0.76 to 2.34; *Correspondence: [email protected] The Assisted Reproduction Center, Northwest Women’s and Children’s Hospital, Affiliated With Xi’an Jiaotong University, Xi’an, China Page 2 of 8Zhang et al. BMC Pregnancy and Childbirth (2022) 22:946 P = 0.321), live birth rate (32.39% vs 45.07%; OR 1.31; 95% CI 0.63 to 2.72, P = 0.463) and cumulative live birth rate (54.90% vs 60.60%; OR 1.01; 95% CI 0.59 to 1.74, P = 0.958).

For infertile women with adenomyosis, these two treatment protocols resulted in similar pregnancy outcomes. Larger, prospective studies are needed in the future.

Adenomyosis, GnRH agonist, GnRH antagonist, IVF, Pregnancy outcomes

Adenomyosis is a common gynecological disease in women of late childbearing age characterized by the existence of endometrial glands and stroma in the myo - metrium and impacts women’ s life quality [1]. With more women postponing pregnancy and the develop - ment of radiography methods such as 2D/3D transvagi - nal ultrasonography [2] and magnetic resonance imaging (MRI) [3], clinicians pay more and more attention to the impact of adenomyosis on infertility. Studies reported that adenomyosis had negative effects to women’s fertility by reducing implantation rate, clinical pregnancy rate, live birth rate and increasing miscarriage rate [4–6]. Moreover, women diagnosed with adenomyo - sis have more obstetric complications such as premature rupture of membrane, preeclampsia and so on [7]. Recently, plenty of studies devote to explore the ideal treatment protocol to infertile women with adenomyo - sis in in-vitro fertilization (IVF) /intracytoplasmic sperm injection (ICSI) involving controlled ovarian hyperstimu - lation (COH) protocols, embryo transfer and pretreat - ment before embryo transfer [8]. However, there is still no consensus on which treatment protocol is the most optimal for these women. Gonadotropin-releasing hormone (GnRH) agonist is not only used in COH protocol but also in the therapy of adenomyosis and endometriosis. Several studies support that in infertile women with adenomyosis, long-acting GnRH agonist protocol achieved better pregnancy out - comes after fresh embryo transfer [9, 10], with potential underlying mechanism, such as decreased expression of cytochrome P450 in adenomyosis lesions [11], down- regulation of circulating estrogen levels by inhibiting hypothalamic-pituitary axis, improved microenviron - ment and follicular quality [12], and ameliorative endo - metrial receptivity by up-regulating Hoxa10, Hoxa11, Lif and integrinβ3 [13]. However, due to possible excessive suppression of hypothalamic-pituitary axis and following poor ovarian response [14], long-acting GnRH agonist protocol is not suitable for all women, especially those with poor ovarian reserve. Recently, the GnRH antago - nist protocol is widely used due to the shorter treatment duration, the lower dose of gonadotropin, and higher patient compliance [15]. During fresh embryo transfer cycles, the supra-physio - logical elevation of estrogen levels in the COH procedure are deleterious to both embryos and endometrium [16]. Moreover, the significantly elevated estrogen levels might aggravate adenomyosis owing to its estrogen-dependent nature. A multicenter, randomized controlled trial (RCT) found that frozen embryo transfer (FET) achieved a higher live birth rate and a lower pregnancy loss rate than fresh embryo transfer in infertile women with polycystic ovary syndrome (PCOS) [17]. However, this finding was not confirmed in ovulatory women [18]. Furthermore, there are only few studies focused on the outcome dif - ferences between fresh embryo transfer cycles and FET cycles in women with adenomyosis [19]. To gain more insight of the most appropriate treatment protocol for infertile women with adenomyosis, we con - ducted this study comparing the pregnancy outcomes in infertile women with ultrasound-diagnosed adenomyo - sis in two treatment protocols, one is GnRH antagonist protocol with freeze-all strategy, the other is long-acting GnRH agonist protocol with fresh embryo transfer.

Study design and population This retrospective cohort study included women with adenomyosis who underwent their first IVF/ICSI cycle at the Northwest Women’s and Children’s Hospital from January 2016 to July 2021. Women with adenomyosis who underwent their first IVF/ICSI cycle with either GnRH antagonist protocol and freeze-all strategy (group A), or long-acting GnRH agonist protocol with fresh embryo transfer (group B) were enrolled. For women in GnRH antagonist protocol, they all received their first FET with hormone replace - ment therapy (HRT) following long-acting GnRH agonist pretreatment, but no specific restriction about GnRH agonist pretreatment in following FET. For women in long-acting GnRH agonist protocol, they all received fresh embryo transfer. The data was collected from electronic medical record system. Women aged above 42 years old, previous sur - gery for adenomyosis, uterine malformation, untreated intrauterine lesions, untreated hydrosalpinx, PCOS, uncontrolled systematic diseases and preimplantation Page 3 of 8 Zhang et al. BMC Pregnancy and Childbirth (2022) 22:946 genetic testing (PGT) cycles were excluded from this study. In total, 282 women were included, 168 women received GnRH antagonist protocol and freeze-all strat - egy and 114 women received long-acting GnRH agonist protocol (Fig. 1). All women had a baseline transvaginal ultrasound prior to commencement of IVF/ICSI. Adenomyosis diag - nosis was based on the standard radiological criteria: (1) enlargement of the uterine corpus, (2) asymmetri - cally thickened myometrium of uterine walls, (3) poor definition of the junctional zone, (4) heterogeneity of the myometrium or hypoechoic striations, and (5) sub- endometrial myometrial cysts [20]. The basal uterine vol- ume was calculated by baseline transvaginal ultrasound screening using a geometric formula: long diameter × width diameter × anteroposterior diameter × π/6 [21]. IVF/ICSI treatment protocols The appropriate COH protocol was offered to women based on their age, body mass index (BMI), antral follicle count (AFC) and menstrual cycle. In women received GnRH-antagonist protocol, COH with daily dosage of gonadotropin (150–300 IU) was initiated on day 2–4 of menstrual cycle, and the dosage was adjusted according to women’s age, BMI, and ovar - ian reserve. GnRH antagonist 0.25 mg /day was given when at least one follicle was ≥12 -14 mm in mean diam- eter until the trigger day (including the trigger day). This group of women received freeze-all strategy and follow - ing FET. The women with long-acting GnRH-agonist proto - col underwent long-acting GnRH agonist (3.75 mg) subcutaneous injection starting on day 2–5 of men - strual cycle for one or more times. The size of uterus was measured 30 days after each injection, if the anter - oposterior diameter exceeded 70 mm, long-acting GnRH agonist would be injected a second time. After 30 days of the last long-acting GnRH agonist injec - tion, once endometrium thickness ≤ 5 mm, serum estradiol≤ 50 pg/mL, and LH ≤ 5 IU/L were confirmed, COH was started with 150–300 IU/day gonadotropin according to women’s age, weight, and ovarian reserve. Women in this group all received fresh embryo transfer. GnRH agonist pretreatment and HRT endometrial preparation in FET Women received one or more times of 3.75 mg long- acting GnRH agonist on day 2 of the cycle after an ultrasound scan confirmed ovarian quiescence and the presence of a thin endometrium (< 5 mm). After 28 to 30 days following the last injection, estradiol Fig. 1 The study flow chart Page 4 of 8Zhang et al. BMC Pregnancy and Childbirth (2022) 22:946 valerate (Progynova; Bayer Schering Pharma AG, Ber - lin, Germany) was administered orally at 4 to 6 mg daily. Approximately 10 to 12 days later, vaginal progesterone was administered to achieve endometrial transforma - tion as soon as the endometrial thickness reached 7 mm and the serum progesterone level was < 1.5 ng/mL. FET was then performed 3 days (cleavage-stage embryos) or 5 days (blastocysts) after progesterone therapy. Study outcomes The primary outcome was live birth rate defined as deliv- ery of neonate ≥28 week’s gestation with heart beat and breath after first embryo transfer. Secondary outcomes were clinical pregnancy rate, miscarriage rate and pre - term delivery rate of first embryo transfer and cumulative live birth rate (CLBR). Clinical pregnancy was defined as the presence of at least one intrauterine gestational sac at approximately 6-week gestation ultrasound. Miscar - riage was defined as fetal delivery at < 28 weeks of gesta - tional age. Preterm delivery was defined as fetal delivery at ≥28 weeks but < 37 weeks of gestational age. All above outcomes were calculated for each patient. The CLBR was calculated by including the first live birth attributable to IVF/ICSI cycle within 12 months after COH, which is the numerator, and the denominator was defined as all women. Statistical method Propensity-score matching (PSM) was performed to adjust for confounding factors related to achieving preg - nancy outcomes, the variables in the PSM included age, BMI, AFC, infertility type and infertility duration, which allowed a part of women in two groups can be matched reciprocally with similar characteristics. To optimize the precision of the study, the match was conducted in a 1:1 matching ratio without replacement, and with a caliper width equal to 0.01 of the standard deviation of the logit of the propensity score. Standardized differences were estimated. Data were expressed as mean ± standard devia - tion (SD), Median (Q1-Q3) or n (%). Descriptive data were compared by Student’s T, Mann–Whitney U, Chi-squared or Fishers’ exact tests when appropriate in original cohort, and paired paired t test, Wilcoxon signed-rank test, and McNemar’s test was used in PSM cohort. Logistic regression was used to compare clinical pregnancy rate, live birth rate after adjusting for several confounders, and conditional logistic regression was used in PSM cohort. We selected these confounders on the basis of their associations with the outcomes of inter - est or a change in effect estimate of more than 10%. Data were analyzed using the statistical packages R (The R Foundation; https://www.r-project.org; version3.4.3) and Empower (R) (www. empow ersta tes. com, X&Y solutions, inc. Boston, Massachusetts). P < 0.05 was considered to be significant.

Baseline characteristics In this study, 282 women with adenomyosis were recruited in original cohort and 142 women in PSM cohort. The baseline characteristics were shown in Table  1. In original cohort, women who received long-acting GnRH agonist protocol were apparently Table 1 Baseline characteristics before and after propensity score matching (PSM) between different treatment protocols Note: Group A = GnRH antagonist protocol and freeze-all strategy; Group B = long-acting GnRH agonist protocol; PSM = propensity-score matching; BMI = body mass index; AFC = antral follicle count Variables Original cohort P PSM cohort P Group A (n = 168) Group B (n = 114) Standardized difference Group A (n = 71) Group B (n = 71) Standardized difference Age (years) 33.62 ± 4.00 31.67 ± 3.64 0.51 < 0.001 32.30 ± 4.07 32.21 ± 3.85 0.02 0.892 BMI (kg/m2) 22.24 ± 3.12 22.85 ± 3.26 0.19 0.115 22.23 ± 2.79 22.18 ± 3.05 0.02 0.913 Basal AFC (n) 7.50 (5.00–10.00) 12.00 (9.00–16.00) 1.13 < 0.001 10.00 (7.00–13.00) 10.00 (7.00–12.00) 0.02 0.687 Infertility duration (years) 3.00 (2.00–4.00) 3.00 (2.00–5.00) 0.02 0.881 2.00 (2.00–4.00) 3.00 (2.00–5.00) 0.02 0.847 Infertility type (n, %) 0.19 0.120 0.06 0.839 Primary 77 (45.83%) 63 (55.26%) 39 (54.93%) 37 (52.11%) Secondary 91 (54.17%) 51 (44.74%) 32 (45.07%) 34 (47.89%) Basal uterine volume (cm3) 97.65(69.65– 141.68) 72.58(52.32– 109.96) – 0.002 97.97 (71.85– 133.77) 71.57 (50.61– 124.65) – 0.023 Co-occurring with endometriosis (n, %) 55 (32.74%) 27 (23.68%) – 0.100 29 (40.85%) 22 (30.99%) – 0.230 Page 5 of 8 Zhang et al. BMC Pregnancy and Childbirth (2022) 22:946 younger (P < 0.001) and had more basal AFC (P < 0.001) and smaller basal uterine volume (P = 0.002) compared to women in GnRH antagonist protocol. No significant differences were found in BMI, infertility duration, infertility type and co-occurring with endometriosis between two groups. After PSM, the baseline charac - teristics between two groups reached a well balance in age, BMI, basal AFC, infertility type and infertility duration with a standardized difference below 10%. However, in PSM cohort, women with long-acting GnRH agonist protocol still had smaller basal uterine volume (P = 0.023). Treatment characteristics in IVF/ICSI Treatment information in two groups were exhibited in Table  2. Before PSM, there was a statistically sig - nificant difference in stimulation duration (P < 0.001), the number of oocytes retrieved (P < 0.001), number of fertilization (P = 0.001), number of 2PN (P = 0.002), number of available embryos (P = 0.011), number of transferred high-quality embryos (P = 0.007) and embryo stage transferred (P = 0.002) between two groups. After PSM, women received long-acting GnRH agonist protocol had higher gonadotropin dosage (P = 0.001) and longer stimulation duration (P < 0.001) compared women with GnRH antagonist protocol. There were no statistically significant differences in other characteristics between the groups. Pregnancy outcomes The pregnancy outcomes were presented in Table  3. In original cohort, compared with women with GnRH antagonist protocol and freeze-all strategy, women using long-acting GnRH agonist protocol conducted higher clinical pregnancy rate (49.40% vs 64.04%), miscar - riage rate (12.50% vs 17.54%), live birth rate (36.90% vs 45.61%), twin pregnancy rate (8.06% vs 19.23%), preterm delivery rate (8.93% vs 13.16%) and CLBR (51.79% vs 64.04%), but only clinical pregnancy rate (P = 0.015) and CLBR (P = 0.042) showed a significantly statistical differ - ence. PSM cohort had similar pregnancy outcomes with original cohort, which showed that clinical pregnancy rate was 46.48% vs 60.56%, miscarriage rate was 14.08% vs 15.49%, live birth rate was 32.39% vs 45.07% and CLBR was 54.90% vs 60.60% between GnRH antagonist proto - col and long-acting GnRH agonist protocol. However, all differences didn’t reach statistical difference in PSM cohort. The results of logistic regression and conditional Table 2 Ovarian stimulation characteristics of two treatment protocols Note: Group A = GnRH antagonist protocol and freeze-all strategy; Group B = long-acting GnRH agonist protocol; PSM = propensity-score matching; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; 2PN = two pronuclear Original cohort P PSM cohort P Group A (n = 168) Group B (n = 114) Group A (n = 71) Group B (n = 71) Gonadotropin dosage (IU) 2639.36 ± 741.08 2697.37 ± 968.87 0.570 2406.69 ± 564.97 2930.28 ± 1040.40 0.001 Duration of stimulation (days) 9.77 ± 1.63 11.84 ± 2.98 < 0.001 9.49 ± 1.29 11.93 ± 3.05 < 0.001 Number of oocytes retrieved (n) 7.00 (4.00–10.00) 10.00 (7.00–12.75) < 0.001 8.00 (6.00–12.50) 9.00 (6.00–12.00) 0.978 Fertilization type (n, %) 0.162 0.431 IVF 144 (85.71%) 88 (77.19%) 62 (87.32%) 57 (80.28%) ICSI 19 (11.31%) 22 (19.30%) 8 (11.27%) 11 (15.49%) IVF + ICSI 5 (2.98%) 4 (3.51%) 1 (1.41%) 3 (4.23%) Number of fertilization (n) 6.00 (4.00–8.00) 8.00 (5.00–10.00) 0.001 7.00 (5.00–10.50) 7.00 (5.00–10.00) 0.606 2PN(n) 4.00 (3.00–7.00) 6.00 (4.00–8.00) 0.002 6.00 (4.00–7.50) 5.00 (4.00–8.00) 0.766 Number of available embryos (n) 4.00 (3.00–6.00) 5.00 (3.00–7.00) 0.011 5.00 (3.00–700) 5.00 (2.50–700) 0.818 Number of high-quality embryos (n) 2.00 (1.00–4.00) 3.00 (2.00–5.00) 0.080 3.00 (2.00–5.00) 3.00 (2.00–5.00) 0.461 Number of transferred embryos (n, %) 0.420 0.263 1 96 (57.14%) 68 (59.65%) 49 (69.01%) 41 (57.75%) 2 72 (42.86%) 45 (39.47%) 22 (30.99%) 29 (40.85%) 3 0 (0.00%) 1 (0.88%) 0 (0.00%) 1 (1.41%) Number of transferred high-quality embryos (n, %) 0.007 0.009 0 69(41.07%) 39(34.21%) 30(42.25%) 24(33.80%) 1 91(54.17%) 57(50.00%) 40(56.34%) 33(46.68%) 2 8(4.76%) 18(15.79%) 1(1.41%) 14(19.72%) Embryo stage (n, %) 0.002 >0.99 Cleavage stage 99 (58.93%) 46 (40.35%) 32 (45.07%) 33 (46.48%) Blastocyst stage 69 (41.07%) 68 (59.65%) 39 (54.93%) 38 (53.52%) Page 6 of 8Zhang et al. BMC Pregnancy and Childbirth (2022) 22:946 logistic regression were presented in Table  4. After adjusting for potential confounders presented in Table  4, no difference was found in live birth between two groups after adjusting for covariates in original cohort (OR 1.10, 95%CI, 0.61 to 2.00, P = 0.753), after PSM (OR 1.39, 95%CI, 0.81 to 2.38, P = 0. 227) and after adjusting for covariates in PSM cohort (OR 1.31, 95%CI, 0.63 to 2.72, P = 0.463). Other pregnancy outcomes were not statisti - cally different in regression analysis (Table 4).

In this study, women receiving fresh embryo transfer after long-acting GnRH agonist protocol reached slightly higher clinical pregnancy rate, live birth rate and CLBR, also higher miscarriage rate and preterm delivery rate in both original cohort and PSM cohort. However, these differences were not statistically significant after adjust - ing confounders. A plenty of studies tried to explore the most appropri - ate treatment protocol to infertile women with adeno - myosis. A meta-analysis found that the long stimulation protocol had better outcomes compared to short stimu - lation protocol in pregnancy rate, live birth, and miscar - riage in adenomyosis women [22]. Studies also showed that women with adenomyosis following the ultra-long GnRH agonist protocol have a better pregnancy out - comes than those following the long GnRH agonist pro - tocol [9, 10]. Thalluri et  al. demonstrated that following GnRH antagonist protocol, compared to infertile women without adenomyosis, women with adenomyosis had apparently lower clinical pregnancy rate [23]. Other stud- ies support that GnRH agonist may improve the preg - nancy outcomes of IVF/ICSI involving fresh embryo transfer or FET [24, 25]. These studies indicated that GnRH agonist treatment seems to get better pregnancy outcomes in women with adenomyosis. Table 3 Pregnancy outcomes of two treatment protocols Note: Group A = GnRH antagonist protocol and freeze-all strategy; Group B = long-acting GnRH agonist protocol; PSM = propensity-score matching Original cohort P PSM cohort P Group A (n = 168) Group B (n = 114) Group A (n = 71) Group B (n = 71) Clinical pregnancy rate (n, %) 83 (49.40%) 73 (64.04%) 0.015 33 (46.48%) 43 (60.56%) 0.130 Miscarriage rate (n, %) 21 (12.50%) 20 (17.54%) 0.238 10 (14.09%) 11 (15.49%) 0.813 Early miscarriage 17(10.12%) 17(14.91%) 0.225 8(11.27%) 10(14.08%) 0.796 Late miscarriage 4(2.38%) 3(2.63%) 0.894 2(2.81%) 1(1.41%) 0.560 Live birth rate (n, %) 62 (36.90%) 52 (45.61%) 0.144 23 (32.39%) 32 (45.07%) 0.168 Single/twin 0.079 0.214 Single (n, %) 57(91.94%) 42(80.77%) 20 (86.96%) 25 (78.12%) Twin (n, %) 5(8.06%) 10(19.23) 3 (13.04%) 7 (21.88%) Preterm delivery rate (n, %) 15 (8.93%) 15 (13.16%) 0.258 5 (7.04%) 11 (15.49%) 0.185 Cumulative live birth rate (n, %) 87/168(51.79%) 73/114(64.04%) 0.042 39/71(54.90%) 43/71(60.60%) 0.610 Table 4 Multivariable logistic regression of pregnancy outcomes in different treatment protocols Note: Group A = GnRH antagonist protocol and freeze-all strategy; Group B = long-acting GnRH agonist protocol; PSM = propensity-score matching; OR = odds ratio; CI = confidence interval; BMI = body mass index; AFC = antral follicle count a No adjustments for covariates b Adjusted for age, BMI, AFC, basal uterine volume, number of transferred embryos, embryo stage, number of transferred high-quality embryos, number of available embryos c Adjusted for basal uterine volume, number of transferred embryos, embryo stage, number of transferred high-quality embryos, number of available embryos d P < 0.05 Pregnancy outcomes Original cohort PSM cohort Crude OR a (95% CI) Adjusted OR b (95% CI) Crude OR a (95% CI) Adjusted OR c (95% CI) Clinical pregnancy rate 1.82(1.12,2.97) d 1.73(0.90,3.32) 1.30(0.83,2.05) 1.28(0.75,2.21) Miscarriage rate 1.49(0.77,2.90) 1.85(0.73,4.71) 1.10(0.47,2.59) 1.27(0.43,3.73) Live birth rate 1.43(0.88,2.33) 1.22(0.65,2.30) 1.39(0.81,2.38) 1.29(0.66,2.54) Preterm delivery rate 1.55(0.72,3.30) 1.53(0.57,4.07) 2.20(0.76,6.33) 2.06(0.52,8.25) Cumulative live birth rate 1.71(1.04,2.82) d 1.17(0.58,2.38) 1.10(0.71,1.70) 0.98(0.58,1.67) Page 7 of 8 Zhang et al. BMC Pregnancy and Childbirth (2022) 22:946 Wu et  al. found that FET following long-term GnRH agonist pretreatment had a higher live birth rate than fresh embryo transfer with a long or ultra-long GnRH agonist protocol [26]. Another study showed that vitri - fied-warmed embryo transfer achieved a higher singleton live birth rate and lower risk of preterm birth than fresh embryo transfer in women with adenomyosis [19], how - ever, this study did not compare different COH protocols. In contrast, our results showed that long-acting GnRH agonist pretreatment before FET in HRT cycle following GnRH antagonist protocol didn’t reach a higher clinical pregnancy rate, live birth rate and CLBR. Previous stud - ies exhibited similar results, which found that long-acting GnRH agonist based on the HRT cycle may not increase the rate of clinical pregnancy or live birth [27]. Severity degree of adenomyosis is a quite important factor which impacts pregnancy outcomes. Research has shown that women with adenomyosis with larger uterine volume before FET might have a lower live birth rate and higher incidence of miscarriage [28]. In this study, women undergoing GnRH antagonist protocol had larger basal uterine volume in both original cohort and PSM cohort, which might partly contribute to the poorer pregnancy outcomes in this group. There are several strengths of this study. Firstly, only women undergoing first IVF/ICSI cycle were included which avoided the selection bias of treatment protocol brought by multiple cycles. Secondly, We adopted inter - nationally accepted criteria for the diagnosis of adenomy- osis through transvaginal ultrasound scans. There are limitations of this study. This is a retrospec - tive study, therefore selection bias cannot be avoided. Moreover, we only used basal uterine volume to repre - sent severity degree of adenomyosis. However, location, scope of adenomyosis lesion and whether endometrium is affected are related to pregnancy outcomes [29]. Fur - thermore, women in GnRH antagonist protocol were older and had less basal AFC than women in long-acting GnRH agonist protocol in this study, since clinicians wouldn’t choose long-acting GnRH agonist protocol for women with less basal AFC to avoid excessive ovarian suppression. PSM was conducted to control these base - line differences between two groups to achieve a rela - tively good balance.

In conclusion, these two treatment protocols to infertile women with adenomyosis resulted in similar pregnancy outcomes. Larger, prospective studies with more detailed information about adenomyosis are needed to further evaluate the ideal treatment protocol among women with adenomyosis undergoing IVF/ICSI. Abbreviations IVF: in-vitro fertilization; ICSI: intracytoplasmic sperm injection; PSM: propensity-score matching; OR: odds ratio; CI: confidence interval; MRI: magnetic resonance imaging; COH: controlled ovarian hyperstimulation; GnRH: Gonadotropin-releasing hormone; RCT : randomized controlled trial; FET: frozen embryo transfer; PCOS: polycystic ovary syndrome; HRT: hormone replacement therapy; PGT: preimplantation genetic testing; BMI: body mass index; AFC: antral follicle count; CLBR: cumulative live birth rate..

We thank all the staff from Northwest Women’s and Children’s Hospital for their assistance and thank all participants in the study. Authors’ contributions LTZ, JZS collected, analysed, interpreted data and drafted the first version of the manuscript. YX, XLL collected data. HC, XTLsupervised data collection and revised the article. All authors approved the final version. The authors read and approved the final manuscript. Funding This research was supported by the National Natural Science Foundation of China (82001543). Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Declarations Ethics approval and consent to participate Written informed consent was obtained from all patients before treatment, and the patients consented to the use of their retrospective data in scientific publications. This study was approved by the Ethics Review Board of the Northwest Women’s and Children’s Hospital, Xi’an, China (No. 2022007). All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Received: 25 August 2022 Accepted: 1 December 2022

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