Identify high-risk DOR women ≤ 35 years old following assisted reproduction technology through cutoffs of anti-mullerian hormone and antral follicle counts.

This was a retrospective cohort study performed at the reproductive medicine center of Wen Zhou Medical University. This study was approved by the Review of Ethics Committee in Clinical Research of the First Affiliated Hospital of Wenzhou Medical University (protocol number, KY2023-R224). We included all women (≤ 35 years of age) who underwent autologous IVF/ICSI and whose first oocyte aspiration cycles occurred from January 2018 to March 2023 ( n  = 11008). The initial included patients were aged 20–35 years and had a normal BMI (19–24 kg/m 2 ) before ovarian stimulation. Females with endometriosis, basic endocrine diseases (diabetes, thyroid disease etc.), immune diseases, or genetic disorders were excluded. Males with genetic disorders, or whose sperms were retrieved by operations were excluded. A total of 10037 patients were ultimately enrolled. The frozen-thawed embryo transfer (FET) outcomes were followed up until December 31, 2023. To identify the young population of high-risk DOR patients, two receiver operating characteristic (ROC) curve analyses were performed: first, ROC curve analysis of the number of oocytes retrieved for predicting one viable embryo obtained (one top-quality embryo or one viable blastocyst), and second, ROC curves of the number of oocytes retrieved for predicting the cutoffs of AMH and AFC. According to our ROC analysis and POSEIDON criteria, young patients were further included and categorized into three groups: (1) DOR patients with AMH values ≤ 1.2 ng/mL and/or with AFC ≤ 5 (according to POSEIDON criteria) were selected as the positive control group, as these patients were most likely to have true depletion of ovarian reserve (DOR group, n  = 1153); (2) patients with AMH values and AFC, which were below the thresholds of ROC analyses in the present study but did not reach the values of POSEIDON criteria, were selected as the study group, as these patients were likely to have mild but not severe depletion of ovarian reserve (high-risk DOR group, n  = 682); and (3) patients with AMH values ranging from 2.5 to 5.5 ng/mL and with AFC ranging from 11 to 20 were selected as the negative control group, as these patients were most likely to have normal ovarian reserve (NOR group, n  = 2649). Women were treated with either the gonadotrophin-releasing hormone (GnRH) agonist protocol, the GnRH antagonist protocol, or the progesterone-primed ovarian protocol for pituitary downregulation. Briefly, in the GnRH agonist protocol, 0.8–3.75 mg depot of gonadotropin-releasing hormone (GnRH) agonist (Diphereline, Ipsen Pharma Biotech, France) was administered in the midluteal phase of the preceding cycle. In the GnRH antagonist protocol, 0.25 mg of cetrorelix (Cetrotide, Merck, Germany) was administered daily from the day the leading follicle was larger than 14 mm until the human chorionic gonadotrophin (hCG) triggering day. Tablet medroxyprogesterone acetate (MPA) (Meprates, Serum Institute of India) 10 mg once daily was started from the second day of menses or from the luteal period until the day of ovulation trigger. Human menopausal gonadotrophin or recombinant follicle-stimulating hormone (FSH) was administered daily to stimulate follicular development, and the starting dose was based on the female’s body mass index (BMI), baseline AFC and AMH. Recombinant human choriogonadotropin alfa (Ovidrel, 250 ug) was used to trigger oocyte maturation and ovulation with a leading mature follicle > 18 mm, or at least 2 follicles > 17 mm, or at least 3 follicles > 16 mm. Transvaginal ultrasound-guided oocyte pickup was performed approximately 36 h after hCG injection. Oocytes were inseminated using in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) depending on semen parameters. Embryo transfer (ET) was performed on day 3 or 5 post aspiration and luteal support was provided with 40 mg of daily intramuscular injections of progesterone and 20 mg of dydrogesterone twice daily from the day of oocytes retrieved. All the embryos were cryopreserved via vitrification. Embryo quality was assessed following the system of morphological assessment described by Simon et al. [ 15 ]. Top-quality D3 embryos were defined as those with less than 20% anucleate fragments with equally or slightly unequally sized blastomeres. All viable blastocysts were defined as top-quality embryos. For FET cycles, hormonal replacement therapy was administered. In all cases, patients were orally administered 2 mg of estradiol valerates (Progynova; Bayer-Schering Pharma AG, Germany) twice daily, which was increased after 4 days to 3 mg twice daily. Transvaginal ultrasound monitoring (SonoScape S15; Kaili Biomedical Technology, China) was performed to assess endometrial thickness approximately 10 days after starting oral estradiol to measure the thickness and pattern of the endometrium. Progesterone was added if the endometrial thickness was greater than 7 mm. If the endometrial thickness was less than 7 mm, estrogen was continuously increased to 4 mg twice daily with/without vaginal administration of micronized E2 (Femoston; Abbott, the Netherlands) for another 5‒7 days. Day 3 embryos or blastocysts were warmed and transferred 3 or 5 days after progesterone administration, respectively. A serum pregnancy test was performed at 11‒13 days after ET in fresh IVF/ICSI cycles. Ultrasound scans were carried out at 6 and 8 weeks of gestation to confirm clinical pregnancy if the serum beta-hCG level was > 10 mIU/mL. CLBR per oocyte aspiration cycle was the primary outcome. The secondary outcomes included the parameters of ovarian response (number of oocytes retrieved, metaphase II (MII) oocytes retrieved, top-quality D3 embryos, viable D3 embryos and viable blastocysts), and pregnancy outcomes per ET (live birth rates, clinical pregnancy rates, ongoing pregnancy rates, and pregnancy loss rates). The CLBR per initiated cycle included all live birth events from the fresh ET and all frozen-thawed ET events derived from this initial cycle. Normal fertilization was confirmed as the presence of two pronuclei on day 1. Pregnancy was defined as a serum beta-hCG level > 10 mIU/mL at 11‒13 days following ET. Clinical pregnancy was defined as an intrauterine gestational sac on transvaginal ultrasound. Ongoing pregnancy was defined as gestation lasting for more than 12 weeks. Live birth was defined as delivering a live baby at ≥ 28 weeks of gestation. PSM was used to control for confounding variables, including age, duration of infertility, BMI and infertility type. The high-risk DOR group was matched by propensity score with the NOR group at a ratio of 1:1 to those in the NOR group and the matching tolerance was set to 0.02. A case-control analysis was subsequently conducted to analyze follicle development and oocyte performance during oocyte aspiration cycles, and the outcomes of fresh ET and FET cycles between the high-risk DOR group and NOR group. Statistical analysis was performed via SPSS 27.0 (SPSS IBM Corp., USA). If continuous variables were distributed normally, the data were expressed as the mean ± standard deviation (SD), and then analyzed by an independent-sample t test (groups = 2) or ANOVA (groups ≥ 3); if not, the data were presented as the median (quartile) and then analyzed by a nonparametric test. The numerical data were expressed as percentages and were analyzed by the chi-square test. ROC analyses were performed via Graphpad version 10 (GraphPad Software Inc., San Diego, CA). The cutoffs of ROC were measured by sensitivity and specificity. Univariate logistic regressions were performed to determine the group allocation affecting the outcomes of IVF/ICSI. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to present the effects of the thresholds of AMH and AFC. A value of p  < 0.05 was considered statistically significant.

A total of 10037 patients (≤ 35 years old) from January 2018 to March 2023 were analyzed for ovarian reserve, including precycle parameters (AMH and AFC) and postcycle parameters (oocyte yield and embryo yield). According to ROC analyses and the POSEIDON criteria, 4484 patients were included and further divided into three groups (1153 patients in the DOR group, 682 patients in the high-risk DOR group, and 2649 patients in the NOR group). The FET outcomes were followed up to December 31, 2023. The outcomes of 5841 ET cycles were analyzed. PSM was conducted to further confirm the differences in ovarian response and pregnancy outcomes between the high-risk DOR group and NOR group. A profile summary of the study is shown in Fig. 1 . Fig. 1 Flow chart of patient selection, grouping and comparisons Flow chart of patient selection, grouping and comparisons In the present study, the ROC curve (Fig. 2 A) of the number of oocytes retrieved for predicting one viable embryo (one top-quality embryo yield or one viable blastocyst) indicated that the threshold of the number of oocytes retrieved was 6.5 (AUC = 0.867, standard error = 0.013, 95% confidence interval: 0.842–0.891, p  < 0.001, sensitivity: 0.875, specificity: 0.733, Youden’s index: 0.608). Additionally, to obtain 6.5 oocytes, ROC curves of the AMH (Fig. 2 B) and AFC (Fig. 2 C) prediction models suggested that the cutoff of AMH was 2.53 ng/mL (AUC = 0.847, standard error = 0.006, 95% CI: 0.829–0.853, p  < 0.001, sensitivity: 0.751, specificity: 0.797, Youden’s index: 0.548) and the cutoff of AFC was 10.5 (AUC = 0.836, standard error = 0.006, 95% CI: 0.822–0.847, p  < 0.001, sensitivity: 0.661, specificity: 0.876, Youden’s index: 0.537). According to the AMH and AFC prediction models in the present study and the POSEIDON criteria, patients were further categorized into three groups: (1) the DOR group (AMH values ≤ 1.2 ng/mL and/or AFC ≤ 5; n  = 1153); (2) the high-risk DOR group (1.2 < AMH values < 2.5 and 5 ≤ AFC ≤ 10; n  = 682); and (3) the NOR group (2.5 ≤ AMH values ≤ 5.5 and/or 11 ≤ AFC ≤ 20; n  = 2249). Fig. 2 Receiver operating characteristic (ROC) curve analyses of the young females younger than 35 years. (A) ROC analysis of the number of oocytes retrieved for predicting one viable embryo obtained (one top-quality embryo or one viable blastocyst); area under the ROC curve (AUC) 0.867 (95% CI: 0.842–0.891), sensitivity 0.875, specificity 0.733, Youden’s index 0.608, p  < 0.001; (B) ROC curve of the number of oocytes retrieved for predicting the cutoff of AMH; AUC 0.847 (95%CI: 0.829–0.853), sensitivity 0.751, specificity 0.797, Youden’s index 0.548, p  < 0.001; (C) ROC curve of the number of oocytes retrieved for predicting the cutoff of AFC; AUC 0.836 (95%CI: 0.822–0.847), sensitivity 0.661, specificity 0.876, Youden’s index 0.537, p  < 0.001 Receiver operating characteristic (ROC) curve analyses of the young females younger than 35 years. (A) ROC analysis of the number of oocytes retrieved for predicting one viable embryo obtained (one top-quality embryo or one viable blastocyst); area under the ROC curve (AUC) 0.867 (95% CI: 0.842–0.891), sensitivity 0.875, specificity 0.733, Youden’s index 0.608, p  < 0.001; (B) ROC curve of the number of oocytes retrieved for predicting the cutoff of AMH; AUC 0.847 (95%CI: 0.829–0.853), sensitivity 0.751, specificity 0.797, Youden’s index 0.548, p  < 0.001; (C) ROC curve of the number of oocytes retrieved for predicting the cutoff of AFC; AUC 0.836 (95%CI: 0.822–0.847), sensitivity 0.661, specificity 0.876, Youden’s index 0.537, p  < 0.001 The baseline characteristics of the patients among the three groups are shown in Table 1 . The patients in the DOR group and in the high-risk DOR group were older than those in the NOR group (all p  < 0.001). The patients in the high-risk DOR group had a longer duration of infertility than those did in the NOR group ( p  < 0.001). There were significant differences in the percentages of primary infertility between the DOR group and NOR group (50.1% vs. 44.1%, p  < 0.014). As expected, there were significant differences on the number of AFC and AMH values among the three groups compared to each other (DOR group < high-risk DOR group < NOR group, all p  < 0.001), and patients in the DOR group had the minimum mean number of AFC (6.47) and lowest mean value of AMH (0.952 ng/mL). Table 1 Characteristics of patients undergoing IVF/ICSI among the three groups DOR High-risk DOR NOR p 1 p 2 p 3 No. of oocyte aspiration cycles, n 1153 682 2649 Age(y), median [IQR] 32 [29-34] 32 [29-34] 30 [28-33] 0.981 <0.001 <0.001 BMI (kg/m 2 ), mean ± SD 21.955±3.194 21.728±3.120 21.800±3.194 0.141 0.168 0.602 Duration of infertility (y), median [IQR] 3 [2-4] 3 [2-5] 3 [2-4] 0.069 0.684 0.017 Primary infertility, n (%) 578 (50.1) 301(44.1) 1257(47.5) 0.014 0.129 0.132 AMH (ng/mL), mean ± SD  0.952±0.892 1.817±0.359 3.819±0.840 <0.001 <0.001 <0.001 AFC on day 3, mean ± SD  6.47±3.705 8.27±1.350 15.55±2.743 <0.001 <0.001 <0.001 Gn duration (d), mean ± SD 10.78±4.518 11.32±2.369 10.90±1.864 <0.001 0.25 <0.001 p1 DOR group vs. high-risk DOR group, p2 DOR group vs. NOR group, p3 High-risk DOR group vs. NOR group, BMI Body mass index, FSH Follicle-stimulating hormone, LH Luteinizing hormone, E2 Estrogen, AMH Anti-Müllerian hormone, AFC Antral follicle count, hMG Human menopausal gonadotropin Characteristics of patients undergoing IVF/ICSI among the three groups p1 DOR group vs. high-risk DOR group, p2 DOR group vs. NOR group, p3 High-risk DOR group vs. NOR group, BMI Body mass index, FSH Follicle-stimulating hormone, LH Luteinizing hormone, E2 Estrogen, AMH Anti-Müllerian hormone, AFC Antral follicle count, hMG Human menopausal gonadotropin The oocyte aspiration cycle characteristics of the patients among the three groups are shown in Table 2 . There were significant differences in the number of retrieved oocytes (5.33 ± 3.790 vs. 8.28 ± 3.890 vs. 14.38 ± 5.765), MII oocytes (4.85 ± 3.297 vs.7.23 ± 3.559 vs. 12.47 ± 5.359), top-quality D3 embryos (1.96 ± 1.731 vs. 2.66 ± 2.036 vs. 4.43 ± 3.009), viable blastocysts in blastocyst culture cycles (1.27 ± 1.562 vs. 1.65 ± 1.870 vs. 2.98 ± 2.773), and viable blastocysts in oocyte aspiration cycles (0.64 ± 1.277 vs. 1.20 ± 1.757 vs. 2.74 ± 2.775) among the three groups (DOR group < high-risk DOR group < NOR group, p  < 0.001). Compared with the high-risk DOR group and NOR group, the DOR had the highest percentages of cycles with no retrieved oocytes (3.38%, p  < 0.001) and no MII oocytes (2.33%, p  < 0.001), but it had the lowest percentages of cycles with viable embryos retrieved (84.39%, p  < 0.001). Table 2 Oocyte aspiration cycle characteristics of the patients among the DOR group, high-risk DOR group and NOR group DOR High-risk DOR NOR p1 p2 p3 Oocytes aspiration  No. of oocyte aspiration cycles, n 1153 682 2649  No. of retrieved oocytes, n, mean ± SD 5.33±3.790 8.28±3.890 14.38±5.765 <0.001 <0.001 <0.001  No. of MII oocytes, n, mean ± SD 4.85±3.297 7.23±3.559 12.47±5.359 <0.001 <0.001 <0.001  Mature oocyte rates, % 88.5 87.4 86.5 0.146 <0.001 0.189  No. of cycles with no oocyte retrieved, n (%) 39 (3.38) 3 (0.44) 5 (0.19) <0.001 <0.001 0.213  No. of cycles with no MII oocyte retrieved, n (%) 26 (2.33) 3 (0.44) 3 (0.11) 0.003 <0.001 0.104 Insemination  Methods of Insemination 1088 676 2641  IVF, n (%) 748 (68.8) 435 (64.4) 1658 (62.8) 0.061 <0.001 0.475  ICSI, n (%) 281 (25.8) 165 (24.4) 549 (20.8) 0.536 <0.001 0.046  Half ICSI, n (%) 59 (5.4) 76 (11.2) 434 (16.4) <0.001 <0.001 0.001 Normal fertilization rates in MII oocyte cycles, %, mean ± SD  IVF (%) 70.8±27.2 69.8±22.0 70.8±21.1 0.448 0.969 0.414  ICSI (%) 75.3±29.8 79.6±21.1 76.1±18.5 0.052 0.617 0.083  Half ICSI (%) 69.5±22.6 75.1±19.3 72.6±16.6 0.070 0.210 0.258 Embryos culture  No. of cycles with viable embryos retrieved, n (%) 973(84.39) 654(95.89) 2618(98.83) <0.001 <0.001 <0.001  No. of top-quality D3 embryos, n, mean ± SD 1.96±1.731 2.66±2.036 4.43±3.009 <0.001 <0.001 <0.001  Top-quality D3 embryo rates, %, mean ± SD 52.1±36.0 50.6±30.7 49.6±25.9 0.318 0.023 0.432  No. of blastocyst culture cycles, n (%) 572 (49.6) 491 (72.0) 2426 (91.6) <0.001 <0.001 <0.001  No. of viable blastocysts in blastocyst culture cycles, n, mean ± SD 1.27±1.562 1.65±1.870 2.98±2.773 0.015 <0.001 <0.001  Blastocyst rates per blastocyst culture cycles, %, mean ± SD 38.4±38.4 37.0±34.4 40.0±28.9 0.665 0.271 0.117  No. of viable D3 embryos, n, mean ± SD 1.84±1.328 2.37±1.245 2.62±1.378 <0.001 <0.001 <0.001  No. of viable blastocysts in oocyte aspiration cycles, n, mean ± SD 0.64±1.277 1.20±1.757 2.74±2.775 <0.001 <0.001 <0.001 p1 DOR group vs. high-risk DOR group, p2 DOR group vs. NOR group, p3 High-risk DOR group vs. NOR group, IVF In-vitro fertilization, ICSI Intracytoplasmic sperm injection, Half ICSI Half number of MII oocytes fertilized by in-vitro fertilization and half number of MII oocytes fertilized by intracytoplasmic sperm injection Oocyte aspiration cycle characteristics of the patients among the DOR group, high-risk DOR group and NOR group p1 DOR group vs. high-risk DOR group, p2 DOR group vs. NOR group, p3 High-risk DOR group vs. NOR group, IVF In-vitro fertilization, ICSI Intracytoplasmic sperm injection, Half ICSI Half number of MII oocytes fertilized by in-vitro fertilization and half number of MII oocytes fertilized by intracytoplasmic sperm injection To evaluate the relative predictive value of group allocation for the number of cycles with viable embryos obtained and cycles with blastocyst culture, logistic regression analyses were performed for the respective populations of each comparison (Fig. 3 ). High-risk DOR was associated with greater odds of the number of cycles with viable embryos obtained (OR 4.321, 95%CI: 2.867–6.513, p  < 0.001) and blastocyst culture cycles (OR 2.611, 95%CI: 2.131–3.199, p  < 0.001) than the DOR group, and with lower odds of the number of cycles with viable embryos obtained (OR 0.277, 95%CI: 0.165–0.464, p  < 0.001) and cycles with blastocyst culture (OR 0.236, 95%CI: 0.190–0.293, p  < 0.001) than the NOR group. Fig. 3 Univariate logistic regression analyses of the associations between group allocation and the outcomes of IVF/ICSI cycles among the three groups Univariate logistic regression analyses of the associations between group allocation and the outcomes of IVF/ICSI cycles among the three groups The outcomes of fresh ET and FET are presented in Table 3 . Compared with those in the NOR group, the live birth rates per total ET, including fresh ET and FET, were significantly lower in the DOR group (39.7% vs. 47.8%, p  < 0.001) and high-risk DOR group (43.2% vs. 47.8%, p  = 0.019). There were significant differences in the percentages of CLBRs per oocyte aspiration cycle among the three groups (43.0% vs. 59.0% vs. 78.2%, p  < 0.001), and the DOR group had the lowest percentage of CLBRs per oocyte aspiration cycle. To investigate the effects of embryo development stage and the effects of whether embryos were frozen, the outcomes of D3 embryos and blastocysts which were frozen-thawed or not, were analyzed separately. Compared with those in the NOR group, the live birth rates per frozen D3 ET were significantly lower in the DOR group (35.9% vs. 47.8%, p  < 0.001) and high-risk DOR group (39.2% vs. 47.8%, p  = 0.004), compared to that of NOR group. Table 3 Pregnancy outcomes of embryo transfer cycles among the three groups DOR High-risk DOR NOR p 1 p 2 p 3 No. of fresh and frozen ET cycles, n 1147 846 3848 Live birth rates per total ETs, % (n) 39.7 (439/1107) 43.2 (356/824) 47.8(1781/3727) 0.123 <0.001 0.019 Live birth rates per fresh D3 ET, %(n) 45.1 (105/233) 46.6 (110/236) 50.6 (359/710) 0.781 0.152 0.294 Live birth rates per frozen D3 ET, %(n) 35.9 (229/638) 39.2 (143/365) 47.8 (633/1324) 0.309 <0.001 0.004 Live birth rates per fresh D5/6 ET, %(n) 54.5 (6/11) 66.7(8/12) 47.3 (43/91) 0.68 0.754 0.235 Live birth rates per frozen D5/6 ET, %(n) 44.0 (99/225) 45.0 (95/211) 46.6 (746/1602) 0.848 0.476 0.714 Cumulative Live birth rates per oocyte aspiration cycles, % (n) 43.0 (439/1021) 59.0 (356/603) 78.2 (1781/2277) <0.001 <0.001 <0.001 No. of removed cases in ET cycles, n 40 22 121 No. of removed cases in oocyte aspiration cycles, n 132 79 372 Lost to follow-up 5 2 14 Gestational duration 35 20 107 No live birth with remained embryos 92 57 251 No. of total D3 ET cycles ， n (%) 894 (77.9) 610 (72.1) 2070 (53.8) 0.003 <0.001 <0.001  No. of removed cases, n (%) 23 (2.6) 9 (1.5) 36 (1.7) 0.202 0.152 0.724  Endometrial thickness on ET day, mean ± SD 10.40±2.09 10.46±2.06 10.41±1.99 0.583 0.896 0.605  No. of transferred embryos per ET, mean ± SD 1.77±0.429 1.88±0.330 1.93±0.265 <0.001 <0.001 0.003  HCG positive rates per ET, % (n) 53.8 (469/871) 56.7 (341/601) 64.4 (1309/2034) 0.287 <0.001 <0.001  Clinical pregnancy rates per ET, % (n) 45.6 (397/871) 49.8 (299/601) 56.3 (1146/2034) 0.124 <0.001 0.004  Ongoing pregnancy rates per ET, % (n) 39.5 (344/871) 43.1 (259/601) 50.2 (1022/2034) 0.178 <0.001 0.002  Pregnancy loss rates per ET, % (n) 15.5 (135/871) 14.6 (88/601) 15.6 (317/2034) 0.658 0.956 0.607  Live birth rates per ET, % (n) 38.3 (334/871) 42.1 (253/601) 48.8 (992/2034) 0.159 <0.001 0.005 HCG-positive cases in total D3 ET cycles 469 341 1309  Biochemical pregnancy rates per HCG-positives, % (n) 12.8 (60/469) 9.7 (33/341) 10.2 (133/1309) 0.182 0.12 0.84  Ectopic pregnancy rates per HCG-positives, % (n) 2.6 (12/469) 2.6 (9/341) 2.3 (30/1309) 1.000 0.86 0.842  Early miscarriage rates per HCG-positives, % (n) 11.3 (53/469) 11.7 (40/341) 9.5 (124/1309) 0.911 0.281 0.223  Late miscarriage rates per HCG-positives, % (n) 2.1 (10/469) 1.8 (6/341) 2.3 (30/1309) 0.802 0.86 0.679  Live birth rates per HCG-positives, % (n) 71.2 (334/469) 74.2 (253/341) 75.8 (992/1309) 0.381 0.055 0.572 No. of total D5/D6 ET cycles, n (%) 253 (22.1) 236 (27.9) 1778 (46.2) 0.003 <0.001 <0.001  No. of removed cases, n (%) 17 (6.7) 13 (5.5) 85 (4.8) 0.707 0.216 0.628  Endometrial thickness on ET day, mean ± SD 10.603±1.978 9.939±1.808 10.217±1.974 <0.001 0.003 0.041  No. of transferred embryos per ET, mean ± SD 1.11±0.315 1.09±0.292 1.13±0.340 0.562 0.311 0.082  HCG positive rates per ET, %(n) 60.2 (142/236) 65.0 (145/223) 65.8 (1114/1693) 0.29 0.094 0.822  Clinical pregnancy rates per ET, % (n) 52.1 (123/236) 57.0 (127/223) 56.5 (957/1693) 0.304 0.208 0.943  Ongoing pregnancy rates per ET, % (n) 45.8 (108/236) 46.6 (104/223) 48.7 (825/1693) 0.852 0.405 0.569  Pregnancy loss rates per ET, % (n) 15.7 (37/236) 18.8 (42/223) 19.2 (325/1693) 0.389 0.213 0.928  Live birth rates per ET, % (n) 44.5 (105/236) 46.2 (103/223) 46.6 (789/1693) 0.778 0.577 0.943 HCG-positive cases in total D5/D6 ET cycles 142 145 1114  Biochemical pregnancy rates per HCG-positives, % (n) 12.7 (18/142) 10.3 (15/145) 13.1 (146/1114) 0.582 0.897 0.361  Ectopic pregnancy rates per HCG-positives, % (n) 0.70 (1/142) 2.1 (3/145) 1.0 (11/1114) 0.622 1.000 0.212  Early miscarriage rates per HCG-positives, % (n) 10.6 (15/142) 15.9 (23/145) 11.8 (132/1114) 0.224 0.682 0.179  Late miscarriage rates per HCG-positives, % (n) 2.10 (3/142) 0.7 (1/145) 3.2 (36/1114) 0.367 0.613 0.114  Live birth rates per HCG-positives, %(n) 73.9 (105/142) 71.0 (103/145) 70.8 (789/1114) 0.599 0.491 1.000 p1 DOR group vs. high-risk DOR group, p2 DOR group vs. NOR group, p3 High-risk DOR group vs. NOR group, ET Embryo transfer, Removed cases in ET cycles include cases “lost to follow-up”, and cases “in the process of the gestation”; Removed cases in oocyte aspiration cycles include cases “lost to follow-up”, cases “in the process of the gestation” and cases “no live birth with remained embryos” Pregnancy outcomes of embryo transfer cycles among the three groups p1 DOR group vs. high-risk DOR group, p2 DOR group vs. NOR group, p3 High-risk DOR group vs. NOR group, ET Embryo transfer, Removed cases in ET cycles include cases “lost to follow-up”, and cases “in the process of the gestation”; Removed cases in oocyte aspiration cycles include cases “lost to follow-up”, cases “in the process of the gestation” and cases “no live birth with remained embryos” Considering that the number of fresh ET cycles was limited, we focused on the effects of embryo development stage (D3 embryo or D5/6 embryo) on IVF/ICSI outcomes. In D3 ET cycles, significant differences were detected in HCG-positive rates per ET (53.8% vs. 64.4% vs. 64.4%), clinical pregnancy rates per ET (45.6% vs. 56.3% vs. 56.3%), ongoing pregnancy rates per ET (39.5% vs. 43.1% vs. 50.2%), and live birth rates per ET (38.3% vs. 42.1% vs. 48.8%) among the three groups compared with each other (DOR group < high-risk DOR group < NOR group, p  < 0.05). Interestingly, the significant difference in live birth rates disappeared in the D3 ET cycles of the positive HCG population. The pregnancy loss rates per ET or per positive HCG did not differ significantly among the three groups in the D3 ET cycles ( p  > 0.05). There were no significant differences in any of the pregnancy outcomes in the blastocyst ET cycles ( p  > 0.05). Logistic regression analyses were further performed to evaluate the relative predictive value of group allocation for live birth chance in total ET cycles, cumulative live birth in oocyte aspiration cycles, the blastocyst ET number/D3 ET number ratio, and pregnancy outcomes of D3 and D5/6 ET (Fig. 3 ). Compared with the NOR group, the high-risk DOR group was associated with lower odds of live birth (OR 0.831, 95%CI: 0.714–0.968, p  < 0.001). Compared with the NOR group, the high-risk DOR group was associated with lower odds of the blastocyst ET/D3 ET ratio (OR 0.450, 95%CI: 0.383–0.530, p  < 0.05); Compared with the DOR group, the high-risk DOR group was associated with higher odds of the blastocyst ET number/D3 ET number ratio (OR 1.367, 95%CI: 1.114–1.678, p  < 0.05). In oocyte aspiration cycles, compared with the NOR group, the high-risk DOR group was associated with lower odds of cumulative live birth cases (OR 0.401, 95%CI: 0.332–0.486, p  < 0.001), whereas the high-risk DOR group was associated with higher odds of cumulative live birth cases compared with the DOR group (OR 1.911, 95%CI: 1.558–2.344, p  < 0.001). Compared with the NOR group, high-risk DOR was associated with lower odds of HCG positive cases (OR 0.726, 95%CI: 0.604–0.874, p  < 0.001), ongoing pregnancy cases (OR 0.750, 95%CI: 0.624–0.901, p  = 0.002) and live birth cases (OR 0.764, 95%CI: 0.635–0.918, p  = 0.005) in D3 ET cycles. In D5 ET cycles, group allocation was not associated with pregnancy outcomes in the respective population of each comparison. As shown in Table 4 , the basic parameters, including age, infertility duration, BMI, and infertility type, were not significantly different after PSM ( p  > 0.05). Table 4 showed that the high-risk DOR group had a significantly lower number of retrieved oocytes (8.23 ± 3.971 vs. 14.54 ± 5.822, p  < 0.001), a lower number of MII oocytes (7.16 ± 3.633 vs. 12.67 ± 5.390, p  < 0.001) and a lower number of top-quality D3 embryos (2.60 ± 2.03 vs. 4.26 ± 3.02, p  < 0.001) than did the NOR group. A lower number of cycles with blastocyst culture was observed in the high-risk DOR group than in the NOR group ( p  < 0.001). In the cycles with blastocyst culture, the number of blastocysts was significantly lower in the high-risk DOR group than in the NOR group (1.55 ± 1.850 vs. 2.18 ± 2.477, p  < 0.001). The number of viable embryos (3.47 ± 2.02 vs. 5.43 ± 2.61, p  < 0.001), including D3 embryos (2.36 ± 1.26 vs. 3.52 ± 1.57, p  < 0.001) and blastocysts (1.11 ± 1.72 vs. 1.91 ± 2.44, p  < 0.001), that could be frozen and transferred in the high-risk DOR group was lower than that in the NOR group. The percentages of cycles with no MII oocyte obtained (1.3% vs. 0.2%, p  = 0.038) and no embryos obtained (4.6% vs. 1.0%, p  < 0.001) were significantly greater in the high-risk DOR group than in the NOR group. Table 4 Baseline characteristics of patients and oocyte aspiration cycle characteristics between the high-risk DOR group and NOR group after propensity score matching High-risk DOR NOR p No. of patients, n 603 603 Age (y), mean ± SD 31.19±2.974 30.96±2.904 0.186 BMI (kg/m 2 ), mean ± SD 21.687±3.140 21.682±2.938 0.978 Duration of infertility (y), mean ± SD 3.546±2.574 3.669±2.400 0.392 Primary infertility, n (%)  269(44.6) 265(43.9) 0.862 AMH (ng/mL), mean ± SD 1.822±0.358 3.817±0.842 <0.001 AFC, mean ± SD 8.28±1.330 15.48±2.809 <0.001 Gn (d), mean ± SD 11.33±2.349 11.37±1.843 <0.001 Oocytes retrieved  No. of oocytes retrieved, n, mean ± SD 8.23±3.971 14.54±5.822 <0.001  No. of MII oocytes retrieved, n, mean ± SD 7.16±3.633 12.67±5.390 <0.001  Mature oocyte rates, % 86.9 86.6 0.698  No. of cycles with no oocyte retrieved, n (%) 3 (0.5) 3 (0.5) 1.000  No. of cycles with no MII oocyte retrieved, n (%) 8 (1.3) 1 (0.2) 0.038 Insemination  Methods of insemination  IVF, n (%) 379 (63.4) 378 (63.2) 1.000  ICSI, n (%) 153 (25.6) 114 (19.1) 0.008  Half ICSI, n (%) 66 (11.0) 106 (17.7) 0.001 Normal fertilization rates per MII oocyte cycles, %, mean ± SD  IVF (%) 69.5±22.6 71.7±16.2 0.115  ICSI (%) 79.2±21.2 74.5±19.4 0.063  Half ICSI (%) 75.8±19.3 74.5±16.5 0.622 Embryos culture  No. of top-quality D3 embryos in oocyte aspiration cycles, n, mean ± SD 2.60±2.03 4.26±3.02 <0.001  Top-quality D3 embryo rates, %, mean ± SD 50.2±30.9 47.3±26.9 0.084  No. of viable embryos in oocyte aspiration cycles, n, mean ± SD 3.47±2.02 5.43±2.61 <0.001  No. of viable D3 embryos in oocyte aspiration cycles, n, mean ± SD 2.36±1.26 3.52±1.57 <0.001  No. of blastocyst culture cycles, n (%) 430 (71.3) 525 (87.1) <0.001  No. of viable blastocyst in blastocyst culture cycles, n, mean ± SD 1.55±1.850 2.18±2.477 <0.001  Blastocyst rates per blastocyst culture cycles, %, mean ± SD 35.0±33.3 31.0±28.5 0.082  No. of viable blastocyst in oocyte aspiration cycles, n, mean ± SD 1.11±1.72 1.91±2.44 <0.001  No. of cycles with blastocysts retrieved, n (%) 277 (45.9) 366 (60.7) <0.001  No. of cycles with no viable embryos retrieved, n (%) 28 (4.6) 6 (1.0) <0.001 IVF In-vitro fertilization, ICSI Intracytoplasmic sperm injection, Half ICSI Half number of MII oocytes fertilized by in-vitro fertilization and half number of MII oocytes fertilized by intracytoplasmic sperm injection; viable embryos include transferred and frozen embryos Baseline characteristics of patients and oocyte aspiration cycle characteristics between the high-risk DOR group and NOR group after propensity score matching IVF In-vitro fertilization, ICSI Intracytoplasmic sperm injection, Half ICSI Half number of MII oocytes fertilized by in-vitro fertilization and half number of MII oocytes fertilized by intracytoplasmic sperm injection; viable embryos include transferred and frozen embryos Logistic regression analyses further revealed (Fig. 4 ) that the high-risk DOR group was associated with lower odds of the number of cycles with viable embryos obtained (OR 0.206, 95%CI: 0.085–0.502, p  < 0.001) and with lower odds of the number of cycles with blastocysts retrieved (OR 0.550, 95%CI: 0.438–0.692, p  < 0.001) than the NOR group was. The difference in the normal fertilization rates between the groups was not significant, although the methods of insemination differed between the groups. Fig. 4 Univariate logistic regression analyses of the associations between group allocation and the outcomes of IVF/ICSI cycles in the high-risk DOR group and NOR group Univariate logistic regression analyses of the associations between group allocation and the outcomes of IVF/ICSI cycles in the high-risk DOR group and NOR group The pregnancy outcomes of fresh ET and FET between the high-risk DOR group and NOR group after PSM are presented in Table 5 . Compared with the NOR group, the high-risk DOR group presented a lower number of mean ET cycles(1.285 ± 0.677 vs. 1.519 ± 0.854, p  < 0.002), lower live birth rates per total number of ET cycles (45.9% vs. 51.1%, p  = 0.035), and lower CLBRs per number of oocyte aspiration cycles (59.0% vs. 77.6%, p  < 0.001). Owing to the lower number of blastocysts obtained in the high-risk DOR group, the percentages of D3 ET cycles (74.3% vs. 69.4, p  = 0.027) differed between the two groups. In the D3 ET cycles, compared with the NOR group, the high-risk DOR group had a significantly lower number of transferred embryos (1.88 ± 0.334 vs. 1.95 ± 0.219, p  < 0.001), lower HCG-positive rates per ET (57.5% vs. 65.1%, p  = 0.007), lower clinical pregnancy rates per ET (50.5% vs. 58.2%, p  = 0.008), lower ongoing pregnancy rates per ET (44.8% vs. 52.7%, p  = 0.007), and lower live birth rates per ET (43.9% vs. 51.3%, p  = 0.011). No significant difference was found in the pregnancy loss rates between the two groups in the D3 ET cycles. In the blastocyst ET cycles, the number of transferred embryos was significantly lower in the high-risk DOR group than in the NOR group (1.10 ± 0.295 vs. 1.28 ± 0.451, p  < 0.001). The HCG-positive rates per ET, clinical pregnancy rates per ET, ongoing pregnancy rates per ET, live birth rates per ET and pregnancy loss rates per ET did not differ between the two groups in terms of the number of blastocyst ET cycles. Interestingly, in the HCG positive cycles, the pregnancy outcomes, including HCG-positive rates per ET, clinical pregnancy rates per ET, ongoing pregnancy rates per ET and live birth rates per ET, did not differ between the two groups in the D3 ET cycles and blastocyst ET cycles. Table 5 Pregnancy outcomes of embryo transfer cycles between the high-risk DOR group and NOR group after propensity score matching High-risk DOR NOR p No. of fresh and frozen cycles, n 775 916 No. of patients, n 603 603 No. of mean ETs in oocytes aspiration cycles, n, mean ± SD 1.285±0.677 1.519±0.854 <0.002 Live birth rates per total ET cycles, %(n) 45.9 (356/775) 51.1 (468/916) 0.035 Cumulative live birth rates per oocytes aspiration cycles, % (n) 59.0 (356/603) 77.6 (468/603) <0.001 No. of D3 ET cycles ， n (%) 576 (74.3) 636(69.4) 0.027  Endometrial thickness on ET day, mean ± SD 10.50±2.00 10.45±1.99 0.700  No. of transferred embryos in ET, mean ± SD 1.88±0.33 1.95±0.22 <0.001  HCG positive rates per ET, % (n) 57.5 (331/576) 65.1 (414/636) 0.007  Clinical pregnancy rates per ET, % (n) 50.5 (291/576) 58.2 (370/636) 0.008  Ongoing pregnancy rates per ET, % (n) 44.8 (258/576) 52.7 (335/636) 0.007  Pregnancy loss rates per ET, % (n) 13.5 (78/576) 13.8 (88/636) 0.933  Live birth rates per ET, % (n) 43.9 (253/576) 51.3 (326/636) 0.011 HCG positive cases in D3 ET cycles, n 331 414  Biochemical pregnancy rates per HCG-positives, % (n) 9.4 (31/331) 9.2 (38/414) 0.998  Ectopic pregnancy rates per HCG-positives, % (n) 2.7 (9/331) 1.4 (6/414) 0.295  Early miscarriage rates per HCG-positives, % (n) 10.0 (33/331) 8.5 (35/414) 0.302  Late miscarriage rates per HCG-positives, % (n) 1.5 (5/331) 2.2 (9/414) 0.594  Live birth rates per HCG-positives, % (n) 76.4 (253/331) 78.7 (326/414) 0.479 No. of D5/D6 ET cycles, n (%) 199 (25.7) 280 (30.6) 0.027  Endometrial thickness on ET day, mean ± SD 9.94±1.76 10.16±1.91 0.205  No. of transferred embryos in ETs, mean ± SD 1.10±0.30 1.28±0.45 <0.001  HCG positive rates per ET, % (n) 64.8 (129/199) 68.6 (192/280) 0.43  Clinical pregnancy rates per ET, % (n) 58.8 (117/199) 59.6 (167/280) 0.925  Ongoing pregnancy rates per ET, % (n) 52.3 (104/199) 51.8 (145/280) 0.926  Pregnancy loss rates per ET, % (n) 13.1 (26/199) 17.9 (50/280) 0.165  Live birth rates per ET, % (n) 51.8 (103/199) 50.7 (142/280) 0.853 HCG-positive cases in D5/6 ET cycles, n 129 192  Biochemical pregnancy rates per HCG-positives, % (n) 7.00 (9/129) 12.5 (24/192) 0.134  Ectopic pregnancy rates per HCG-positives, % (n) 2.30 (3/129) 0.50 (1/192) 0.306  Early miscarriage rates per HCG-positives, % (n) 10.1 (13/129) 11.5 (22/192) 0.72  Late miscarriage rates per HCG-positives, % (n) 0.80 (1/129) 1.60 (3/192) 0.651  Live birth rates per HCG-positives, % (n) 79.8 (103/129) 74.0 (142/192) 0.232 Pregnancy outcomes of embryo transfer cycles between the high-risk DOR group and NOR group after propensity score matching Logistic regression analyses were performed between the high-risk DOR group and NOR group after PSM (Fig. 4 ). Compared with NOR group, the high-risk DOR group was associated with lower odds of HCG-positive cases (OR 0.725, 95%CI: 0.574–0.913, p  = 0.007), clinical pregnancy cases (OR 0.734, 95%CI: 0.585–0.920, p  = 0.008), ongoing pregnancy cases (OR 0.729, 95% CI: 0.581–0.913, p  = 0.007), and live birth cases (OR 0.745, 95%CI: 0.594–0.933, p  = 0.011) in D3 ET cycles. In D5 ET cycles, group allocation was not associated with pregnancy outcomes between the high-risk DOR group and NOR group. Compared with the NOR group, the high-risk DOR was associated with lower odds of live birth cases in all ET cycles (OR 0.813, 95%CI: 0.671–0.985, p  = 0.035). Compared with the NOR group, the high-risk DOR had lower odds of cumulative live births in oocyte aspiration cycles (OR 0.416, 95%CI: 0.323–0.534, p  < 0.001).

In summary, our study is the first to identify young infertile women with mildly reduced ovarian reserve, through the combined measurements of AMH and AFC. The values of AMH ranging from 1.2 to 2.5 and AFC ranging from 6 to 10 appeared to constitute meaningful thresholds to target the above young women. The results could guide clinicians to better provide proper counseling services for young infertile couples with DOR/high-risk DOR, which are different from aged patients with DOR. Since the present study was retrospective, these findings need to be confirmed in future prospective studies or randomized controlled trials.

For the first time, the present study identified a population of high-risk DOR patients (1.20 ng/mL < AMH values < 2.50 ng/mL, with 6 ≤ AFC ≤ 10; n  = 682) on the basis of ROC analyses and the POSEIDON criteria. Their outcomes were further compared to those of DOR patients (positive control, AMH values ≤ 1.2 ng/mL, and/or AFC ≤ 5; n  = 1153) and NOR patients (negative control, 2.5 ng/mL ≤ AMH values ≤ 5.5 ng/mL, and 11 ≤ AFC ≤ 20; n  = 2649). Additionally, patients with high-risk DOR could achieve relatively higher CLBRs than those with DOR, and there were fewer with no oocytes retrieved, no MII oocytes retrieved, and no embryos obtained versus patients with DOR, all of which ultimately reduce the heavy burden on young infertile patients. The results also revealed that AMH and AFC could serve as predictors for oocyte quantity and the ovarian response to stimulation, but could not effectively predict oocyte quality in young females (≤ 35 years old). All the above comparisons between the high-risk DOR and NOR results were further confirmed by PSM. The ovarian response was clinically evaluated according to the number of retrieved oocytes, MII oocytes, top-quality D3 embryos, viable D3 embryos and viable blastocysts and the percentages of cycles with no oocytes retrieved, no MII oocytes retrieved, and nonviable embryos obtained. DOR usually exhibited POR. As expected, the number of retrieved oocytes, MII oocytes, top-quality D3 embryos, viable D3 embryos, and viable blastocysts significantly decreased, and the percentages of cycles with no oocyte retrieval, and no MII oocyte retrieval significantly increased in DOR and high-risk DOR females (Table 3 ), which was associated with the degree of depletion of the ovarian oocyte pool. These results indicated that DOR, even mildly decreased ovarian reserve, could predict a poor ovarian response in young females. Comparisons between the high-risk DOR and NOR groups after PSM were conducted, and the results were consistent with those observed between the two groups before PSM (Table 4 ). Recently, some studies have shown similar results in young DOR females [ 11 , 12 ]. A study by Morin et al. revealed that the numbers of retrieved oocytes, 2PNs embryos, and usable blastocysts were significantly lower in young DOR patients (< 38 years old), as determined by the values of AMH and by the number of obtained oocytes, than in the control group [ 11 ]. Chang et al. reported that the number of retrieved eggs was significantly lower in the young DOR group (< 37 years old) than that in the control group [ 12 ]. The patients included in the above studies were older than the females included in the present study. Owing to a depleted ovarian oocyte pool, early-onset DOR in young females also results in a decrease in the number of obtained oocyte or embryos, which is consistent with the findings in DOR aged patients [ 13 , 16 ]. Recently, a large-scale retrospective study revealed that AMH was strongly associated with CLBR in women with a reduced ovarian reserve independent of age [ 6 ]. The greater the number of oocytes retrieved was, the greater the CLBR; however, the trend was evident up to 41 years of age, and no clear benefit was observed when the females were older than 44 years of age [ 16 ]. There was a positive correlation between the CLBR and the number of frozen embryos [ 17 , 18 ]. Fewer cryopreserved embryos reduced the chance of ET [ 17 ]. In the present study, high-risk DOR patients had higher CLBR than DOR patients did but had lower CLBR than NOR patients did, which might be due to the differences in the number of available embryos among the three groups. Additionally, our logistic regression analysis revealed that the cumulative live birth chances of DOR patients decreased to 20.1% of those of NOR patients; meanwhile, the cumulative live birth chances of high-risk DOR patients declined to 40.0% of those of NOR patients (Fig. 3 ), indicating that patients with mildly decreased ovarian reserves, such as patients in the high-risk DOR group, should begin to consider receiving fertility assistance and not wait until being diagnosed with DOR before ART interventions. The comparison between the high-risk DOR group and the DOR group was further confirmed by PSM. Thus, a decreased ovarian reserve could be a negative marker of the quantity of the oocytes and embryos, which is associated with a decrease in the CLBR, and the cutoff values of AMH and AFC for predicting high-risk DOR could lead to more valuable information for clinicians and patients in making proper decisions. Embryo quality was clinically assessed on the basis of the fertilization condition, high-quality D3 embryo rates and blastocyst rates, together with pregnancy outcomes (HCG-positive rates, pregnancy rates, ongoing pregnancy rates, live birth rates, and pregnancy loss rates). No significant differences were found in the fertilization conditions, blastocyst rates, or pregnancy loss rates between D3 ET cycles and blastocyst ET cycles among the three groups. The top-quality D3 embryo rates were not lower in the DOR/high-risk DOR than those in the NOR. These findings suggested that young females with DOR/high-risk DOR had a decreased ovarian response to stimulation, but little corresponding effect on the quality of embryos. Interestingly, our results revealed that only DOR and high-risk DOR were negatively correlated with the pregnancy outcomes, including HCG-positive rates, clinical pregnancy rates, ongoing pregnancy rates, and live birth rates, in D3 ET cycles; moreover, the correlation disappeared in blastocyst ET cycles (Table 3 ). Additionally, the live birth rates per positive HCG did not differ among the three groups in either D3 ET cycles or blastocyst cycles, suggesting that once embryonic implantation occurred, DOR/high-risk DOR did not disturb pregnancy development. These results were consistent with those of previous publications [ 3 , 9 , 11 , 12 ]. However, some of these studies did not analyze the pregnancy outcomes of D3 ET cycles and blastocyst ET cycles separately [ 3 , 12 ]. The study by Morin et al. focused on the pregnancy outcomes of blastocyst transfer and revealed that young women with evidence of accelerated follicular depletion presented equivalent blastocyst rates, aneuploidy rates and live birth rates per euploid ET as age-matched controls with a normal precycle (AMH ranging from 1.1 ng/mL to 4.5 ng/mL) and postcycle parameters (the number of retrieved oocytes ranged from 10 to 21) [ 11 ]. Thus, the quality of the embryo was not associated with DOR or high-risk DOR. On the basis of the findings of the present study and previous studies, the cultivation of all D3 embryos to blastocysts is recommended, even if DOR/high-risk DOR females (≤ 35 years old) have fewer D3 embryos. Decreased fertility is related to advanced age, which is accompanied by a reduction in the quantity of oocytes and the quality of oocytes, and with an increased incidence of embryonic aneuploidy [ 19 , 20 ]. However, recently, previous evidence has demonstrated that women older than 34 years of age face a steep increase in the aneuploidy rates [ 21 , 22 ], and the CLBR gradually decreases with increasing female age, especially in females older than 35 years [ 23 , 24 ]. However, the majority of studies have reported the pregnancy outcomes of females with a diminished ovarian reserve who were less than 37 or 38 years of age [ 11 , 12 , 25 ]. Thus, to separate age-related decreases in oocyte quality and to differentiate age-related increases in embryonic aneuploidy, the patients included in the present study were younger than 35 years old. Previous studies have demonstrated that aneuploidy is an important factor in the spontaneous miscarriage [ 26 ]. The present study revealed that DOR and high-risk DOR were not associated with pregnancy loss rates (biochemical pregnancy rates, ectopic pregnancy rates, early miscarriage rates and late miscarriage rates) (Table 3 ), further indirectly demonstrating that aneuploidy might not play a key role in the young population ( ≤  35 years of age) with DOR/high-risk DOR. There were strengths and weaknesses in the present study. To our knowledge, this first large-scale study is the first to determine the thresholds of AMH and AFC in the females younger than 35 years with mildly diminished ovarian reserve. However, this study was retrospective; thus, prospective or interventional studies should be conducted to better address these problems. Another limitation of this study was that the transferred embryos were not tested by preimplantation genetic testing for aneuploidy (PGT-A), although previous studies have demonstrated that the incidence of embryonic aneuploidy dose not increase in the women younger than 35 years [ 21 , 22 ]. The conditions of the ovarian stimulation protocols and cancellation of ovarian stimulation cycles were not checked in the manuscript.

Diminished ovarian reserve (DOR) and poor ovarian response (POR) to stimulation, which are used to indicate poor predictive performance, are increasing, but intractable issues in reproductive medicine [ 1 , 2 ]. Hu et al. have reported that approximately 6.3% of infertile women younger than 35 years were diagnosed with DOR or POR [ 3 ]. Up to one-third of patients with DOR suffer a POR to ovarian stimulation resulting in cycle cancellation and a reduced chance of a live birth [ 4 ]. Currently, age, baseline follicular stimulating hormone (FSH), anti-Mullerian hormone (AMH), antral follicle count (AFC), and inhibin-B have been widely applied in clinical practice and used to predict ovarian reserve [ 1 , 5 – 7 ]. DOR/POR manifests with a reduced AFC, and/or increased serum FSH and/or decreased AMH [ 2 ]. According to the POSEIDON standard, AMH, AFC and the number of oocytes retrieved after ovarian stimulation, are the most commonly used biomarkers for determining the ovarian reserve and ovarian response to stimulation [ 8 ]. Females with DOR must resort to assisted reproductive technology (ART), such as in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). An increasing number of studies have focused on the pregnancy outcomes of women with DOR/POR who resort to IVF/ICSI. Some studies have shown that advanced female patients with DOR have low pregnancy rates and high rates of pregnancy loss, as well as decreased live birth rates [ 9 , 10 ]. Some studies have demonstrated that in young patients with either prestimulation evidence of DOR or POR to stimulation, there is no qualitative decline in oocyte performance and there are no negative effects on pregnancy outcomes [ 11 , 12 ]. Among young women (< 35 years old) with DOR, the mean cumulative live birth rate (CLBR) per oocyte aspiration cycle was lower than 36.1% [ 6 , 13 ]. A low CLBR increases the mental, physical, and economic burdens on this young population of patients [ 12 ]. However, the pregnancy outcomes of young infertile patients whose ovarian reserve is declining but has not yet met the POSEIDON criteria for DOR, termed high-risk DOR in the present study, have not been investigated. To alleviate the heavy burden of infertile young women, we aimed to identify a young population of high-risk DOR patients through AMH and AFC, and further used pregnancy outcomes to test the fertility of the above suspected subfertile females. The CLBR is considered a preferable measure of the success of IVF/ICSI treatment [ 14 ], and thus CLBR served as the primary pregnancy outcome in the present study. Women with normal ovarian reserve were regarded as the negative control group, and those with DOR were regarded as the positive control group. Additionally, the outcomes were compared between high-risk DOR and patients with normal ovarian reserve after PSM, controlling for confounding variables, including age, duration of infertility, BMI and infertility type.