Obstetric outcomes following artificial and natural cycle frozen embryo transfer in patients with and without endometriosis: a national cohort study

This study utilized data from the National Health Insurance Service (NHIS), which operates under the Ministry for Health, Welfare, and Family Affairs in the Republic of Korea. The NHIS serves as the primary medical insurer for approximately 97% of the Korean population [ 14 ]. To facilitate reimbursement, healthcare utilization data from all medical institutions were submitted and stored in the NHIS database. This comprehensive database, established in January 2002, includes information from every hospital, covering both inpatient and outpatient records classified according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and claims for healthcare services and pharmacy dispensing, coded by the Health Insurance Review and Assessment Service of Korea. Data were obtained from a research database of the NHIS (NHIS-2023-1616). Since October 2017, infertility treatments have been covered under health insurance in Korea; thus, the dataset used in this study included all NHIS claims records from October 2017 to December 2021. Individual identifiers in the Korean NHIS database were anonymized. The study was approved by the official assessment panel of the Korean Government and the Institutional Review Board of Pusan National University Hospital (IRB 2304-015-126) in accordance with their guidelines. Because the data were de-identified, the Institutional Review Board waived the need for informed consent. Figure 1 presents a flowchart of the study participants. This study focused on women with singleton pregnancies, using data from the NHIS. In vitro fertilization (IVF) pregnancies were identified based on the ET procedural codes (R6530-6533, R6540, and R6550) recorded within 90 days of the initial pregnancy diagnosis. Only the first pregnancy during the study period was included in the analysis. FETs were distinguished based on the presence of embryo thawing procedural codes (R6502). These FETs were then categorized into two groups according to prescription records: the artificial cycle (AC)-FET group, which included women prescribed estradiol within 30 days before ET, and the natural cycle (NC)-FET group, which included true natural cycles and modified natural cycles, where no prescriptions were given or patients received human chorionic gonadotropin, clomiphene, letrozole, follicle-stimulating hormone, or human menopausal gonadotropin within 30 days before ET. The endometriosis and non-endometriosis groups were distinguished based on a diagnosis with ICD-10 code N80 within 1 year of a confirmed pregnancy, which included all subtypes of endometriosis. A previous study reported that diagnostic codes in Korea’s claims data demonstrated a high positive predictive value [ 15 ]. During the study period, the majority of endometriosis cases in Korea were diagnosed following surgical confirmation, in accordance with the standard clinical practice at that time. In certain cases, diagnoses may have been established using ultrasound or magnetic resonance imaging. Fig. 1 Flow diagram showing the distribution of the study population. Abbreviations: IVF/ICSI, in vitro fertilization/intracytoplasmic sperm injection; FET, frozen embryo transfer; ET, embryo transfer; AC-FET, artificial cycle-frozen embryo transfer; NC-FET, natural cycle-frozen embryo transfer Flow diagram showing the distribution of the study population. Abbreviations: IVF/ICSI, in vitro fertilization/intracytoplasmic sperm injection; FET, frozen embryo transfer; ET, embryo transfer; AC-FET, artificial cycle-frozen embryo transfer; NC-FET, natural cycle-frozen embryo transfer Pregnancy and obstetric outcomes were identified using ICD-10 diagnostic codes. Pregnancy outcomes included abortion (O00–O06), defined as termination of pregnancy before fetal viability (<20 weeks’ gestation or fetal weight <500 g), and further classified as spontaneous abortion (miscarriage), induced abortion (artificial termination), or ectopic pregnancy; preterm birth (Z3700–Z3701, Z3790–Z3791, O6010–O6011, O6030–O6031) as live birth before 37 completed weeks; term birth (Z3702, Z3792) as live birth at ≥37 weeks; and stillbirth (Z371) as fetal death at ≥20 weeks or birth weight ≥500 g. Obstetric complications comprised threatened abortion (O200: vaginal bleeding through a closed cervical os before 20 weeks); hypertensive disorders of pregnancy (O11, O13–O15), including gestational hypertension (O13: BP ≥140/90 mm Hg after mid-pregnancy without proteinuria) and preeclampsia (O11, O14–O15: hypertension with proteinuria); placenta previa (O44: placental implantation in the lower uterine segment, covering or near the internal cervical os); placenta accreta (O432: abnormal villous adherence to the myometrium); and postpartum hemorrhage (O72: ≥1,000 mL blood loss or blood loss with hypovolemic signs within postpartum). Additional outcomes included gestational diabetes mellitus (O244: carbohydrate intolerance first recognized in pregnancy); preterm labor (O602: regular contractions before 37 weeks with cervical change); preterm premature rupture of membranes (O42: spontaneous membrane rupture before 37 weeks and labor onset); incompetent cervix (O343: painless cervical dilatation in the second trimester); cesarean section (O82); and emergency cesarean section (O821). Covariates included maternal age at the index date, calendar year (categorical), obstetric history, and medical history within one year prior to the initial pregnancy confirmation. Obstetric and medical history was assessed using ICD-10 codes for hypertension (I10–I15), diabetes mellitus (E10–E14), and polycystic ovary syndrome (E282), dyslipidemia (E78), autoimmune diseases (M05–M06, M32–M35, M45, M79, D56, D89, K50–K51, L40), asthma (J45–J46), hypothyroidism (E02–E03), hyperthyroidism (E05), depressive disorders (F32–F33), anxiety disorders (F40–F41), bipolar disorder (F30–F31), gravida≥1, and recurrent pregnancy loss (N91, O262). The chi-square test was used to compare groups based on categorical data, the one-way analysis of variance or Kruskal-Wallis test for continuous variables. while adjusted odds ratios (aORs) and 95% CIs were obtained from multivariable binary logistic regression adjusted for maternal age, calendar year (categorical), and obstetric/medical history (gravida≥1, recurrent pregnancy loss, hypertension, diabetes mellitus, polycystic ovarian syndrome, dyslipidemia, thyroid disease, asthma, autoimmune disease, depressive disorder, anxiety disorder, bipolar disorders). To assess whether the effect of AC-FET versus NC-FET differed between the groups with and without endometriosis, the p-value for the interaction was used. Visualization was executed using a forest plot and a two-sided test was conducted with a significance level set at 0.05. Furthermore, 1:1 matching was performed using PSM, and propensity scores were calculated based on baseline characteristics and other variables that may affect pregnancy and obstetric outcomes using logistic regression models. All statistical analyses were conducted using the SAS Enterprise Guide version 7.15 (2017, SAS Institute Inc., Cary, NC, USA) and R statistical language version 4.3.1 (2023, R Core Team, R Foundation for Statistical Computing, Vienna, Austria).

Between October 2017 and December 2021, a total of 44,118 singleton pregnant women who underwent IVF and subsequently underwent either delivery or abortion were identified. Among these, 3,817 women (8.7%) were diagnosed with endometriosis. Of those diagnosed, 1,638 women (42.9%) underwent frozen-thawed embryo transfer, with AC-FET being the most common, accounting for 54.7% of the cycles, followed by natural cycle frozen embryo transfer (NC-FET) at 45.3%. In the endometriosis group, the mean maternal age was significantly lower in the AC-FET group (35.6 years) than in the NC-FET group (36.2 years). No significant differences were observed in endometriosis phenotype between the two groups. The rate of recurrent pregnancy loss was higher in the AC-FET group than in the NC-FET group (9.4% vs. 5.7%, p<0.05). Histories of hypertension, diabetes mellitus, polycystic ovary syndrome, dyslipidemia, autoimmune disease, asthma, thyroid disorders, and depressive disorders did not differ significantly between groups (Table 1 ). Table 1 Characteristics of singleton pregnancies depending on endometrial preparation methods in endometriosis patients All N  = 1638 AC-FET N  = 896 NC-FET N  = 742 P value No. of cycles in the index year  2017 10 (0.6) 5 (0.6) 5 (0.7) 0.009  2018 296 (18.1) 150 (16.7) 146 (19.7)  2019 444 (27.1) 254 (28.3) 190 (25.6)  2020 543 (33.2) 321 (35.8) 222 (29.9)  2021 345 (21.1) 166 (18.5) 179 (24.1) Maternal age (y)  < 30 54 (3.3) 33 (3.7) 21 (2.8) 0.064  30–34 580 (35.4) 332 (37.1) 248 (33.4)  35–39 710 (43.3) 389 (43.4) 321 (43.3)  ≥ 40 294 (17.9) 142 (15.8) 152 (20.5) Maternal mean age 35.9 (3.8) 35.6 (3.7) 36.2 (3.8) 0.001 Endometriosis phenotype  Superficial endometriosis 192 (11.7) 101 (11.3) 91 (12.3) 0.586  Deep endometriosis 64 (3.9) 36 (4.0) 28 (3.8) 0.900  Ovarian endometrioma 800 (48.8) 434 (48.4) 366 (49.3) 0.758  Adenomyosis 788 (48.1) 438 (48.9) 350 (47.2) 0.521  Otherwise 330 (20.1) 197 (22.0) 133 (17.9) 0.048 Obstetric history  Gravida ≥ 1 102 (6.2) 57 (6.4) 45 (6.1) 0.885  Recurrent pregnancy loss 126 (7.7) 84 (9.4) 42 (5.7) 0.007 Past medical history  Hypertension 36 (2.2) 20 (2.2) 16 (2.2) 1.000  Diabetes 51 (3.1) 30 (3.3) 21 (2.8) 0.647  PCOS 250 (15.3) 127 (14.2) 123 (16.6) 0.202  Dyslipidemia 388 (23.7) 224 (25.0) 164 (22.1) 0.189  Autoimmune disease 871 (53.2) 476 (53.1) 395 (53.2) 1.000  Asthma 273 (16.7) 154 (17.2) 119 (16.0) 0.579  Hypothyroidism 428 (26.1) 243 (27.1) 185 (24.9) 0.344  Hyperthyrodism 80 (4.9) 37 (4.1) 43 (5.8) 0.149  Depression disorders 74 (4.5) 42 (4.7) 32 (4.3) 0.807  Anxiety disorders 183 (11.2) 116 (12.9) 67 (9.0) 0.015  Bipolar disorders 11 (0.7) 4 (0.4) 7 (0.9) 0.357 Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, PCOS : Polycystic ovarian syndrome Data are presented as number of patients (%) or the mean (SD) A P value < 0.05 was considered statistically significant, as indicated in bold Characteristics of singleton pregnancies depending on endometrial preparation methods in endometriosis patients Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, PCOS : Polycystic ovarian syndrome Data are presented as number of patients (%) or the mean (SD) A P value < 0.05 was considered statistically significant, as indicated in bold Among women diagnosed with endometriosis, no statistically significant differences were observed in the risks of miscarriage, preterm birth, or term birth between the AC-FET and NC-FET groups. In contrast, in the non-endometriosis group, AC-FET was associated with an increased risk of miscarriage (aOR 1.10, 95% confidence interval [CI] 1.03–1.18) and a decreased term birth rate (aOR 0.93, 95% CI 0.87–0.99) compared with NC-FET. There was no evidence of statistical interaction for any of the pregnancy outcomes assessed (Table 2 ). Table 2 Comparison of pregnancy outcomes between AC-FET and NC-FET in endometriosis and non-endometriosis patients Pregnancy outcomes group AC-FET event (%) NC-FET event (%) Crude OR (95% CI) P for interaction Adjusted OR (95% CI) P for interaction Abortion ES 324 (36.2) 266 (35.8) 1.01 (0.83–1.24) 0.586 1.09 (0.88–1.34) 0.801 Non-ES 3209 (33.1) 2206 (31.5) 1.07 (1.01–1.15) 1.10 (1.03–1.18) Ectopic pregnancy ES 47 (5.2) 39 (5.3) 1.00 (0.65–1.54) 0.730 1.02 (0.66–1.59) 0.764 Non-ES 350 (3.6) 274 (3.9) 0.92 (0.78–1.08) 0.93 (0.79–1.09) Miscarriage ES 290 (32.4) 241 (32.5) 0.99 (0.81–1.23) 0.383 1.07 (0.86–1.32) 0.572 Non-ES 2931 (30.3) 1983 (28.3) 1.10 (1.02–1.17) 1.12 (1.05–1.20) Artificial abortion ES 24 (2.7) 10 (1.3) 2.02 (0.96–4.24) 0.443 1.98 (0.93–4.19) 0.455 Non-ES 206 (2.1) 101 (1.4) 1.48 (1.17–1.89) 1.47 (1.16–1.88) Preterm birth ES 22 (2.5) 14 (1.9) 1.46 (0.61–3.49) 0.657 1.36 (0.56–3.32) 0.485 Non-ES 115 (1.2) 75 (1.1) 1.00 (0.69–1.44) 0.99 (0.69–1.43) < 34 weeks ES 6 (0.7) 9 (1.2) 0.66 (0.18–2.47) 0.287 0.74 (0.19–2.89) 0.420 Non-ES 41 (0.4) 29 (0.4) 1.13 (0.60–2.12) 1.12 (0.59–2.10) < 37 weeks ES 17 (1.9) 5 (0.7) 2.78 (0.76–10.14) 0.096 2.44 (0.65–9.14) 0.129 Non-ES 75 (0.8) 47 (0.7) 0.93 (0.60–1.46) 0.93 (0.59–1.46) Term birth ES 548 (61.2) 462 (62.3) 0.95 (0.78–1.17) 0.780 0.89 (0.73–1.10) 0.996 Non-ES 6364 (65.7) 4715 (67.4) 0.93 (0.87–0.99) 0.91 (0.85–0.97) Still birth ES 2 (0.2) 1 (0.1) 1.66 (0.15–18.32) 0.915 3.13 (0.10–95.50) 0.972 Non-ES 8 (0.1) 3 (0.0) 1.93 (0.51–7.26) 1.87 (0.49–7.12) Live birth ES 562 (62.7) 470 (63.3) 0.94 (0.76,-1.18) 0.790 0.87 (0.72–1.06) 0.985 Non-ES 6433 (66.4) 4765 (68.1) 0.93 (0.87-1.00) 0.91 (0.84–1.01) Adjusted OR were adjusted for age, calendar year (categorical), obstetric history and past medical history Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, ES Endometriosis, Non-ES Non-endometriosis, OR Odds ratio, CI Confidence interval Data are presented as number of patients (%) or odds ratio (95% CI) A P value < 0.05 was considered statistically significant and was indicated in bold Comparison of pregnancy outcomes between AC-FET and NC-FET in endometriosis and non-endometriosis patients 1.09 (0.88–1.34) 1.07 (1.01–1.15) 1.10 (1.03–1.18) 1.00 (0.65–1.54) 1.02 (0.66–1.59) 0.92 (0.78–1.08) 0.93 (0.79–1.09) 0.99 (0.81–1.23) 1.07 (0.86–1.32) 1.10 (1.02–1.17) 1.12 (1.05–1.20) 2.02 (0.96–4.24) 1.98 (0.93–4.19) 1.48 (1.17–1.89) 1.47 (1.16–1.88) 1.46 (0.61–3.49) 1.36 (0.56–3.32) 1.00 (0.69–1.44) 0.99 (0.69–1.43) 0.66 (0.18–2.47) 0.74 (0.19–2.89) 1.13 (0.60–2.12) 1.12 (0.59–2.10) 2.78 (0.76–10.14) 2.44 (0.65–9.14) 0.93 (0.60–1.46) 0.93 (0.59–1.46) 0.95 (0.78–1.17) 0.89 (0.73–1.10) 0.93 (0.87–0.99) 0.91 (0.85–0.97) 1.66 (0.15–18.32) 3.13 (0.10–95.50) 1.93 (0.51–7.26) 1.87 (0.49–7.12) 0.94 (0.76,-1.18) 0.87 (0.72–1.06) 0.93 (0.87-1.00) 0.91 (0.84–1.01) Adjusted OR were adjusted for age, calendar year (categorical), obstetric history and past medical history Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, ES Endometriosis, Non-ES Non-endometriosis, OR Odds ratio, CI Confidence interval Data are presented as number of patients (%) or odds ratio (95% CI) A P value < 0.05 was considered statistically significant and was indicated in bold Obstetric complications were analyzed among patients with and without endometriosis who delivered. In the endometriosis group, 572 women underwent AC-FET and 476 underwent NC-FET, whereas in the non-endometriosis group, 6,485 underwent AC-FET and 4,793 underwent NC-FET. In patients with endometriosis, the risk of threatened abortion (aOR 2.10, 95% CI 1.58–2.80), HDP (aOR 2.02, 95% CI 1.11–3.70), and placenta previa (aOR 1.75, 95% CI 1.18–2.60) was higher in the AC-FET group than in the NC-FET group (Table 3 ). In the non-endometriosis group, AC-FET was also associated with increased risks of threatened abortion (aOR 1.50, 95% CI 1.38–1.64), HDP (aOR 1.35, 95% CI 1.16–1.58), placenta previa (aOR 1.26, 95% CI 1.07–1.47), placenta accreta (aOR 2.40, 95% CI 1.45–3.97), and PPH (aOR 1.51, 95% CI 1.30–1.75) compared with NC-FET. Table 3 Comparison of obstetric complications between AC-FET and NC-FET in endometriosis and non-endometriosis patients Obstetric outcome group AC-FET event (%) NC-FET event (%) Crude OR (95% CI) P for interaction Adjusted OR (95% CI) P for interacttion Threatened abortion ES 201 (35.1) 100 (21.0) 2.04 (1.54–2.69) 0.046 2.10 (1.58–2.80) 0.046 Non-ES 2017 (31.1) 1,102 (23.0) 1.51 (1.39–1.65) 1.50 (1.38–1.64) HDP ES 38 (6.6) 20 (4.2) 1.81 (1.01–3.27) 0.344 2.02 (1.11–3.70) 0.360 Non-ES 564 (8.7) 311 (6.5) 1.35 (1.16–1.57) 1.35 (1.16–1.58) Gestational HT ES 19 (3.3) 11 (2.3) 1.45 (0.68–3.08) 0.975 1.76 (0.81–3.84) 0.976 Non-ES 355 (5.5) 186 (3.9) 1.43 (1.20–1.72) 1.44 (1.19–1.73) Preeclampsia ES 19 (3.3) 9 (1.9) 1.78 (0.80–3.98) 0.397 1.84 (0.80–4.20) 0.443 Non-ES 209 (3.2) 125 (2.6) 1.24 (0.99–1.56) 1.24 (0.99–1.55) Placenta previa ES 83 (14.5) 43 (9.0) 1.71 (1.16–2.53) 0.145 1.75 (1.18–2.60) 0.163 Non-ES 422 (6.5) 253 (5.3) 1.25 (1.06–1.47) 1.26 (1.07–1.47) Placenta accreta ES 12 (2.1) 5 (1.1) 2.02 (0.71–5.77) 0.782 1.92 (0.66–5.58) 0.758 Non-ES 64 (1.0) 20 (0.4) 2.38 (1.44–3.94) 2.40 (1.45–3.97) PPH ES 58 (10.1) 34 (7.1) 1.47 (0.94–2.28) 0.911 1.49 (0.95–2.33) 0.872 Non-ES 560 (8.6) 283 (5.9) 1.51 (1.30–1.75) 1.51 (1.30–1.75) GDM ES 116 (20.3) 101 (21.2) 0.95 (0.70–1.28) 0.768 0.92 (0.64–1.32) 0.864 Non-ES 1,348 (20.8) 1,004 (20.9) 0.99 (0.09–1.09) 0.90 (0.81–1.01) IIOC ES 47 (8.2) 28 (5.9) 1.41 (0.88–2.28) 0.324 1.42 (0.87–2.32) 0.351 Non-ES 338 (5.2) 224 (4.7) 1.09 (0.92–1.30) 1.09 (0.92–1.29) Preterm labor ES 187 (32.7) 162 (34.0) 0.94 (0.73–1.22) 0.556 0.94 (0.72–1.22) 0.499 Non-ES 1,880 (29.0) 1,369 (28.6) 1.02 (0.94–1.11) 1.01 (0.93–1.10) PPROM ES 99 (17.3) 88 (18.5) 0.92 (0.67–1.27) 0.448 0.88 (0.64–1.22) 0.393 Non-ES 1,135 (17.5) 806 (16.8) 1.05 (0.95–1.16) 1.04 (0.95–1.15) CS ES 219 (38.3) 149 (31.3) 1.36 (1.05–1.76) 0.441 1.39 (1.07–1.82) 0.365 Non-ES 2,017 (31.1) 1,291 (26.9) 1.23 (1.13–1.33) 1.24 (1.14–1.35) Emergency CS ES 70 (12.2) 49 (10.3) 1.22 (0.83–1.79) 0.901 1.20 (0.81–1.79) 0.882 Non-ES 639 (9.9) 386 (8.1) 1.25 (1.09–1.42) 1.24 (1.09–1.42) Adjusted OR were adjusted for age, calendar year (categorical), obstetric history and past medical history Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, ES Endometriosis, Non-ES Non-endometriosis, OR Odds ratio, CI Confidence interval, HDP Hypertensive disorders of pregnancy, HT Hypertension, PPH Postpartum hemorrhage, GDM Gestational diabetes mellitus, PPROM Preterm premature rupture of membranes, CS Cesarean section Data are presented as number of patients (%) or odds ratio (95% CI) A P value < 0.05 was considered statistically significant and was indicated in bold Comparison of obstetric complications between AC-FET and NC-FET in endometriosis and non-endometriosis patients 201 (35.1) 100 (21.0) 2.04 (1.54–2.69) 2.10 (1.58–2.80) 2017 (31.1) 1,102 (23.0) 1.51 (1.39–1.65) 1.50 (1.38–1.64) 38 (6.6) 20 (4.2) 1.81 (1.01–3.27) 2.02 (1.11–3.70) 564 (8.7) 311 (6.5) 1.35 (1.16–1.57) 1.35 (1.16–1.58) 19 (3.3) 11 (2.3) 1.45 (0.68–3.08) 1.76 (0.81–3.84) 355 (5.5) 186 (3.9) 1.43 (1.20–1.72) 1.44 (1.19–1.73) 19 (3.3) 9 (1.9) 1.78 (0.80–3.98) 1.84 (0.80–4.20) 209 (3.2) 125 (2.6) 1.24 (0.99–1.56) 1.24 (0.99–1.55) 83 (14.5) 43 (9.0) 1.71 (1.16–2.53) 1.75 (1.18–2.60) 422 (6.5) 253 (5.3) 1.25 (1.06–1.47) 1.26 (1.07–1.47) 12 (2.1) 5 (1.1) 2.02 (0.71–5.77) 1.92 (0.66–5.58) 64 (1.0) 20 (0.4) 2.38 (1.44–3.94) 2.40 (1.45–3.97) 58 (10.1) 34 (7.1) 1.47 (0.94–2.28) 1.49 (0.95–2.33) 560 (8.6) 283 (5.9) 1.51 (1.30–1.75) 1.51 (1.30–1.75) 116 (20.3) 101 (21.2) 0.95 (0.70–1.28) 0.92 (0.64–1.32) 1,348 (20.8) 1,004 (20.9) 0.99 (0.09–1.09) 0.90 (0.81–1.01) 47 (8.2) 28 (5.9) 1.41 (0.88–2.28) 1.42 (0.87–2.32) 338 (5.2) 224 (4.7) 1.09 (0.92–1.30) 1.09 (0.92–1.29) 187 (32.7) 162 (34.0) 0.94 (0.73–1.22) 0.94 (0.72–1.22) 1,880 (29.0) 1.02 (0.94–1.11) 1.01 (0.93–1.10) 99 (17.3) 88 (18.5) 0.92 (0.67–1.27) 0.88 (0.64–1.22) 1,135 (17.5) 806 (16.8) 1.05 (0.95–1.16) 1.04 (0.95–1.15) 219 (38.3) 149 (31.3) 1.36 (1.05–1.76) 1.39 (1.07–1.82) 2,017 (31.1) 1.23 (1.13–1.33) 1.24 (1.14–1.35) 70 (12.2) 49 (10.3) 1.22 (0.83–1.79) 1.20 (0.81–1.79) 639 (9.9) 386 (8.1) 1.25 (1.09–1.42) 1.24 (1.09–1.42) Adjusted OR were adjusted for age, calendar year (categorical), obstetric history and past medical history Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, ES Endometriosis, Non-ES Non-endometriosis, OR Odds ratio, CI Confidence interval, HDP Hypertensive disorders of pregnancy, HT Hypertension, PPH Postpartum hemorrhage, GDM Gestational diabetes mellitus, PPROM Preterm premature rupture of membranes, CS Cesarean section Data are presented as number of patients (%) or odds ratio (95% CI) A P value < 0.05 was considered statistically significant and was indicated in bold Specifically, the absolute risk of threatened abortion was 35.1% in the AC-FET group and 21.0% in the NC-FET group among women with endometriosis, compared with 31.1% and 23.0%, respectively, among those without endometriosis. The aOR for threatened abortion was 2.10 (95% CI, 1.58–2.80) in the endometriosis group versus 1.50 (95% CI, 1.38–1.64) in the non-endometriosis group, with a significant interaction (P = 0.046; Table 3 ). After propensity score matching, baseline characteristics were well balanced between the endometriosis and non-endometriosis groups, with all standardized mean differences below 0.1 (Table 4 ). In the non-endometriosis group, the increased risk of miscarriage and the decreased term birth rate showed similar tendencies but were no longer statistically significant (Supplementary Table 1). For obstetric complications, the aORs were largely consistent with those observed in the unmatched analysis, indicating stable effect sizes. Importantly, the interaction between endometriosis status and treatment method for threatened abortion was no longer statistically significant (P for interaction = 0.695), although the effect direction and magnitude remained comparable to the unmatched analysis (Table 5 ). Table 4 Baseline characteristics of the endometriosis and non-endometriosis groups Before PSM After PSM non-ES ES P SMD non-ES ES P SMD 16684 1638 1638 1638 No. of cycles in the index year < 0.001 0.188 0.826 0.043  2017 148 (0.9) 10 (0.6) 16 (1.0) 10 (0.6)  2018 4211 (25.2) 296 (18.1) 289 (17.6) 296 (18.1)  2019 4410 (26.4) 444 (27.1) 449 (27.4) 444 (27.1)  2020 5010 (30.0) 543 (33.2) 540 (33.0) 543 (33.2)  2021 2905 (17.4) 345 (21.1) 344 (21.0) 345 (21.1) Age (mean (SD)) 35.26 (3.83) 35.86 (3.78) < 0.001 0.159 35.85 (3.79) 35.86 (3.78) 0.897 0.005 Obstetric history  RPL 1172 (7.0) 126 (7.7) 0.340 0.026 126 (7.7) 126 (7.7) 1.000 < 0.001  Gravida ≥ 1 1151 (6.9) 102 (6.2) 0.329 0.027 105 (6.4) 102 (6.2) 0.886 0.008 Past medical history  Hypertension 514 (3.1) 51 (3.1) 1.000 0.002 51 (3.1) 51 (3.1) 1.000 < 0.001  Diabetes 914 (5.5) 91 (5.6) 0.941 0.003 87 (5.3) 91 (5.6) 0.817 0.011  PCOS 4490 (26.9) 323 (19.7) < 0.001 0.171 330 (20.1) 323 (19.7) 0.793 0.011  Dyslipidemia 3128 (18.7) 388 (23.7) < 0.001 0.121 363 (22.2) 388 (23.7) 0.319 0.036  Autoimmune disease 8050 (48.2) 871 (53.2) < 0.001 0.099 899 (54.9) 871 (53.2) 0.344 0.034  Asthma 2510 (15.0) 273 (16.7) 0.087 0.044 240 (14.7) 273 (16.7) 0.124 0.055  Hypothyroidism 3551 (21.3) 428 (26.1) < 0.001 0.114 434 (26.5) 428 (26.1) 0.843 0.008  Hyperthyroidism 714 (4.3) 80 (4.9) 0.279 0.029 85 (5.2) 80 (4.9) 0.749 0.014  Depression disorders 727 (4.4) 74 (4.5) 0.811 0.008 81 (4.9) 74 (4.5) 0.621 0.02  Anxiety disorders 1631 (9.8) 183 (11.2) 0.078 0.046 182 (11.1) 183 (11.2) 1.000 0.002  Bipolar disorders 104 (0.6) 11 (0.7) 0.943 0.006 13 (0.8) 11 (0.7) 0.838 0.014 Propensity score matching by age, timing of the first confirmed pregnancy, obstetric history and comorbidities Abbreviations: non-ES Non-endometriosis, ES Endometriosis, RPL Recurrent pregnancy loss, PCOS Polycystic ovarian syndrome Data are presented as number of patients (%) or odds ratio (95% CI) A P value < 0.05 was considered statistically significant and was indicated in bold Table 5 Summary of obstetric outcomes between AC-FET and NC-FET before and after propensity score matching Outcomes group Before PSM After PSM aOR (95% CI) P for interaction aOR (95% CI) P for interaction Threatened abortion ES 2.10 (1.58–2.80) 0.046 2.09 (1.57–2.77) 0.695 non-ES 1.50 (1.38–1.64) 1.83 (1.38–2.44) HDP ES 2.02 (1.11–3.70) 0.360 2.02 (1.11–3.70) 0.725 non-ES 1.35 (1.16–1.58) 1.69 (1.05–2.72) Gestational HT ES 1.76 (0.81–3.84) 0.976 1.76 (0.81 – 3.83) 0.722 non-ES 1.44 (1.19–1.73) 1.97 (1.10–3.55) Preeclampsia ES 1.84 (0.80–4.20) 0.443 1.85 (0.81 – 4.22) 0.806 non-ES 1.24 (0.99–1.55) 1.45 (0.74 – 2.85) Placenta previa ES 1.75 (1.18–2.60) 0.163 1.83 (1.22–2.72) 0.097 non-ES 1.26 (1.07–1.47) 0.98 (0.56 – 1.69) Placenta accreta ES 1.92 (0.66–5.58) 0.758 1.88 (0.64 – 5.47) 0.920 non-ES 2.40 (1.45–3.97) 2.00 (0.51 – 7.89) PPH ES 1.49 (0.95–2.33) 0.872 1.44 (0.93 – 2.26) 0.718 non-ES 1.51 (1.30–1.75) 1.20 (0.77 – 1.89) GDM ES 0.92 (0.64–1.32) 0.864 0.92 (0.64 – 1.32) 0.365 non-ES 0.90 (0.81–1.01) 1.14 (0.80 – 1.63) IIOC ES 1.42 (0.87–2.32) 0.351 1.42 (0.87 – 2.32) 0.418 non-ES 1.09 (0.92–1.29) 1.03 (0.61 – 1.75) Preterm labor ES 0.94 (0.72–1.22) 0.499 0.94 (0.72 – 1.22) 0.775 non-ES 1.01 (0.93–1.10) 0.98 (0.75 – 1.28) PPROM ES 0.88 (0.64–1.22) 0.393 0.89 (0.65 – 1.23) 0.889 non-ES 1.04 (0.95–1.15) 0.90 (0.66 – 1.22) CS ES 1.39 (1.07–1.82) 0.365 1.37 (1.05–1.79) 0.595 non-ES 1.24 (1.14–1.35) 1.52 (1.16–1.98) Emergency CS ES 1.20 (0.81–1.79) 0.882 1.22 (0.81 – 1.81) 0.111 non-ES 1.24 (1.09–1.42) 1.94 (1.24–3.04) Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, ES Endometriosis, Non-ES Non-endometriosis, OR Odds ratio, CI Confidence interval, HDP Hypertensive disorders of pregnancy, HT Hypertension, PPH Postpartum hemorrhage, GDM Gestational diabetes mellitus, PPROM Preterm premature rupture of membranes, CS Cesarean section Data are presented as odds ratio (95% CI) Propensity score matching by age, timing of the first confirmed pregnancy, obstetric history and comorbidities. Adjusted OR were adjusted for age, calendar year (categorical), obstetric history and past medical history. A P value < 0.05 was considered statistically significant and was indicated in bold Baseline characteristics of the endometriosis and non-endometriosis groups 148 (0.9) 10 (0.6) 16 (1.0) 10 (0.6) 4211 (25.2) 289 (17.6) 4410 (26.4) 449 (27.4) 5010 (30.0) 540 (33.0) 2905 (17.4) 344 (21.0) 35.26 (3.83) 35.85 (3.79) 1172 (7.0) 126 (7.7) 126 (7.7) 126 (7.7) 1151 (6.9) 102 (6.2) 105 (6.4) 102 (6.2) 514 (3.1) 51 (3.1) 51 (3.1) 51 (3.1) 914 (5.5) 91 (5.6) 87 (5.3) 91 (5.6) 4490 (26.9) 330 (20.1) 3128 (18.7) 363 (22.2) 8050 (48.2) 899 (54.9) 2510 (15.0) 240 (14.7) 3551 (21.3) 434 (26.5) 714 (4.3) 80 (4.9) 85 (5.2) 80 (4.9) 727 (4.4) 74 (4.5) 81 (4.9) 74 (4.5) 1631 (9.8) 183 (11.2) 182 (11.1) 104 (0.6) 11 (0.7) 13 (0.8) Propensity score matching by age, timing of the first confirmed pregnancy, obstetric history and comorbidities Abbreviations: non-ES Non-endometriosis, ES Endometriosis, RPL Recurrent pregnancy loss, PCOS Polycystic ovarian syndrome Data are presented as number of patients (%) or odds ratio (95% CI) A P value < 0.05 was considered statistically significant and was indicated in bold Summary of obstetric outcomes between AC-FET and NC-FET before and after propensity score matching Abbreviations: AC-FET Artificial cycle-frozen embryo transfer, NC-FET Natural cycle-frozen embryo transfer, ES Endometriosis, Non-ES Non-endometriosis, OR Odds ratio, CI Confidence interval, HDP Hypertensive disorders of pregnancy, HT Hypertension, PPH Postpartum hemorrhage, GDM Gestational diabetes mellitus, PPROM Preterm premature rupture of membranes, CS Cesarean section Data are presented as odds ratio (95% CI) Propensity score matching by age, timing of the first confirmed pregnancy, obstetric history and comorbidities. Adjusted OR were adjusted for age, calendar year (categorical), obstetric history and past medical history. A P value < 0.05 was considered statistically significant and was indicated in bold Within the NC-FET group, cycles were further classified into true natural cycles (tNC; without medication) and modified natural cycles (mNC; with hCG or gonadotropin/hMG support). A total of 457 women with endometriosis and 3,985 without endometriosis underwent tNC, while 285 women with endometriosis and 3,011 without endometriosis underwent mNC. Among women with endometriosis, the risk of HDP was significantly higher in the mNC group compared with the tNC group (aOR 3.54, 95% CI 1.22–10.26), whereas no other pregnancy or obstetric outcomes differed significantly. In the non-endometriosis group, mNC-FET was associated with a reduced risk of miscarriage and an increased rate of term birth (aOR 1.26, 95% CI 1.13–1.40), but also with an elevated risk of HDP (aOR 1.34, 95% CI 1.04–1.71). However, when directly comparing the effect of endometriosis status on HDP risk, no statistically significant interaction was observed between groups (P for interaction = 0.099) (Supplementary table 2).

The findings revealed that, while AC-FET showed no significant differences in pregnancy outcomes compared with NC-FET, it was associated with an increased risk of adverse obstetric outcomes, including threatened abortion, HDP and placenta previa, in patients with endometriosis (Figure 2 ). Notably, the risk of threatened abortion was significantly higher in endometriosis patients compared to those without endometriosis, as indicated by a significant interaction (P = 0.046). Specifically, among women with endometriosis, the absolute risk was 35.1% in the AC-FET group and 21.0% in the NC-FET group, compared with 31.1% and 23.0%, respectively, among women without endometriosis. These findings suggest that both the absolute and relative increases in the risk of threatened abortion were greater for AC-FET in the endometriosis group compared with the non-endometriosis group, and that the combination of endometriosis and AC-FET may confer an additive effect on this risk. Although the odds ratio for threatened abortion appeared higher in the endometriosis group (aOR 2.09) than in the non-endometriosis group (aOR 1.83) after propensity score matching, the interaction test did not reach statistical significance. Due to inherent limitations of the NHIS database, important confounders such as BMI, embryo quality and numbers could not be included in the matching process. Nevertheless, effect directions and magnitudes were broadly consistent before and after matching, supporting the robustness of the primary findings and underscoring the clinical importance of the increased risk of threatened abortion associated with AC-FET in these patients. Larger studies with more detailed clinical information are warranted to clarify whether endometriosis modifies the impact of AC-FET on the risk of threatened abortion. Moreover, our subgroup analysis of NC-FET cycles showed largely comparable outcomes between true and modified natural protocols —with the exception of HDP, which was higher with mNC among women with endometriosis—although the mNC–HDP association did not differ significantly by endometriosis status (P for interaction = 0.099), suggesting that, overall, the choice between them may not substantially influence most pregnancy or obstetric risks. Fig. 2 Adjusted odds ratios comparing AC-FET with NC-FET for pregnancy and obstetric outcomes, stratified by endometriosis (ES vs non-ES). Points denote aORs and horizontal lines 95% confidence intervals; the x-axis is logarithmic. P for interaction values are from a single multivariable logistic model including an AC-FET× endometriosis interaction term and adjusted for maternal age, calendar year (categorical), and obstetric/medical history. Statistically significant p-values (two-sided α=0.05) are shown in bold. Abbreviations: ES, endometriosis; non-ES, non-endometriosis; FET, frozen embryo transfer; AC, artificial cycle; NC, natural cycle; aOR. adjusted odds ratio Adjusted odds ratios comparing AC-FET with NC-FET for pregnancy and obstetric outcomes, stratified by endometriosis (ES vs non-ES). Points denote aORs and horizontal lines 95% confidence intervals; the x-axis is logarithmic. P for interaction values are from a single multivariable logistic model including an AC-FET× endometriosis interaction term and adjusted for maternal age, calendar year (categorical), and obstetric/medical history. Statistically significant p-values (two-sided α=0.05) are shown in bold. Abbreviations: ES, endometriosis; non-ES, non-endometriosis; FET, frozen embryo transfer; AC, artificial cycle; NC, natural cycle; aOR. adjusted odds ratio Two recent cohort studies—Yang et al. and Guo et al.—published in 2023 compared endometrial preparation regimens in women with endometriosis [ 12 , 13 ]. Yang et al. reported no significant differences in miscarriage or live birth rates between AC-FET and NC-FET, findings that are consistent with our null results for pregnancy outcomes; however, their analysis did not extend to obstetric complications [ 12 ]. Guo et al. likewise observed pregnancy outcomes comparable to ours but found no difference in the risk of HDP between AC-FET and NC-FET [ 13 ]. This apparent discrepancy may be attributable to the markedly smaller NC-FET sample size in their study (n = 30), which likely limited statistical power to detect differences, particularly for uncommon outcomes. In contrast, our investigation included substantially larger NC-FET cohorts (endometriosis: n= 476; non-endometriosis: n= 4,793) and evaluated obstetric complications using interaction analyses, thereby enabling more precise effect estimates and a clearer assessment of potential effect modification by endometriosis status. One of the key findings of this study is that AC-FET had a greater impact on the risk of threatened abortion in endometriosis patients compared to non-endometriosis patients. Threatened abortion has been linked to corpus luteum dysfunction [ 16 ], and a previous study conducted in the general population demonstrated an increased risk of threatened abortion in AC-FET cycles [ 17 ]. In the present study, however, endometriosis itself appeared to confer an additional risk when combined with AC-FET. A prospective cohort study similarly reported that women with endometriosis have an increased risk of threatened abortion compared with those without endometriosis [ 18 ]. Although few studies have specifically examined the risk of threatened abortion in patients with endometriosis, the established associations of endometriosis with increased risks of miscarriage, PPROM, and preterm birth [ 19 – 22 ] suggest a plausible indirect link to the heightened risk of threatened abortion. Importantly, despite the elevated risk of threatened abortion in our study, the overall risk of miscarriage was not significantly increased in endometriosis patients. This suggests that while endometriosis itself contributes to early pregnancy instability, it may not necessarily lead to pregnancy loss in all cases. One possible explanation is that medical interventions, such as progesterone supplementation, might have been implemented, particularly in South Korea, where healthcare accessibility is high, potentially mitigating the risk of progression from threatened abortion to miscarriage. In South Korea, luteal phase s with progesterone is considered routine practice in ART, as reflected in Korean tertiary-center studies and local journals that explicitly describe progesterone luteal phase supplementations widely accepted or routine in fresh and frozen embryo transfer cycles. However, because progesterone formulations for ART are often non-reimbursable, their use is not captured in NHIS claims, which include insured items only [ 23 – 25 ]. Nevertheless, the increased risk of threatened abortion itself remains clinically significant, highlighting the importance of close monitoring and appropriate management in endometriosis patients undergoing AC-FET. In our study population, adenomyosis coexisted in less than half of the women with endometriosis. Because adenomyosis has been reported to adversely affect reproductive outcomes in ART, its presence in a substantial proportion of our cohort may have influenced the observed associations. In adenomyosis, GnRHa is often used for pituitary downregulation to improve reproductive conditions [ 23 ]. Our study did not account for GnRHa use, and previous research has reported mixed results. One study in adenomyosis patients undergoing AC-FET found no significant differences in clinical pregnancy rates (40.63% vs. 42.54%, p=0.72) or live birth rates (23.75% vs. 23.75%, p=0.74) between those with and without pretreatment [ 26 ]. Conversely, other studies have shown lower miscarriage rates and higher clinical pregnancy, ongoing pregnancy rates and live birth in the GnRHa group [ 27 , 28 ]. These findings highlight the need for future research stratifying endometriosis patients by concomitant adenomyosis status and GnRHa use to clarify their potential impact on AC-FET outcomes. Given that adenomyosis and endometriosis share overlapping pathophysiological features—such as hormonal resistance and inflammatory changes—the mechanisms underlying the increased risk of threatened abortion in our study are likely complex and multifactorial. Notably, progesterone resistance and changes in uterine contractility in endometriosis can lead to insufficient endometrial receptivity and potentially cause miscarriage [ 19 , 20 ]. Furthermore, patients with endometriosis have been reported to exhibit increased expression of inflammatory pathways, prostaglandins, and activation of metalloproteinases, which result in cervical ripening, collagen breakdown, uterine contractions, and membrane inflammation [ 29 , 30 ]. Such dysregulation of inflammatory molecules in the uteroplacental environment increases the risk of PROM or preterm birth in these women [ 29 , 31 , 32 ]. Furthermore, several hypotheses have been proposed regarding the association of abnormal placentation with endometriosis. One hypothesis posits that an environment of progesterone resistance and altered contractility in endometriosis can delay implantation beyond the window of receptivity. Deferred implantation can result in misguided embryo placement and implantation, leading to placenta previa, ectopic placentation (placenta accreta), or placental insufficiency [ 19 ]. Moreover, the uterine junctional zone serves as the site of placentation during pregnancy [ 10 ]. Suboptimal placentation may arise from defective spiral artery remodeling at the junctional zone of the myometrial–endometrial interface. This defect, in conjunction with the size of the placental bed and the distribution of the spiral artery transformation within the placental bed, may favor central rather than peripheral placentation [ 33 , 34 ]. The primary strength of this study is its design, which, unlike previous research that was either limited to endometriosis populations or compared patients with and without endometriosis in the context of ART versus natural conception, directly compared endometriosis and non-endometriosis cohorts according to the type of endometrial preparation used during the FET cycle. This approach allowed us to distinguish whether adverse pregnancy and obstetric outcomes were attributable to endometriosis itself or to the endometrial preparation method used during the FET protocol. By incorporating an interaction analysis, we were able to assess whether the effect of preparation method differed by endometriosis status, providing clinically relevant insights for tailoring FET protocol selection according to patient characteristics. Furthermore, the use of a large-scale national cohort, encompassing a broad and representative population with minimal selection bias, enabled a robust evaluation of these associations with adequate statistical power. However, this strength is tempered by notable limitations inherent to the NHIS database. A primary limitation is the inability to access detailed clinical records. For example, the database lacks comprehensive information on pre-pregnancy BMI, detailed prior obstetric history, pre-pregnancy maternal medical history, including surgical findings and stage of endometriosis, severity of threatened abortion, ART methods, stimulation protocols, embryonic stages and embryonic quality—all of which could potentially influence pregnancy and obstetric outcomes. In particular, higher pre-pregnancy BMI is linked to adverse obstetric outcomes, including preeclampsia/HDP and preterm birth [ 35 , 36 ]. Moreover, because the extent and depth of endometriotic lesions have been associated with differential impacts on implantation, placentation, and obstetric outcomes, the inability to control for these factors may have introduced residual confounding. Information on whether patients received medical or surgical treatment for endometriosis prior to FET and use of a GnRHa–AC regimen was not available, as this variable was not considered at the study design stage. This omission may also have introduced residual confounding. In addition, the number of previous embryo transfers, and the type of FET performed before the study period was not accessible, as infertility treatment has only been covered by insurance since October 2017. Future studies incorporating clinical records, or treatment history would allow more accurate disease characterization, minimize potential confounding, and enable outcome comparisons across severity subgroups.Another limitation is the possibility of underreporting or misclassification of diagnoses and procedures. Nevertheless, the large and comprehensive nature of the NHIS dataset has mitigated these concerns. Finally, rare outcomes such as placenta accreta showed relatively high point estimates but were accompanied by wide confidence intervals (e.g., placenta accreta: aOR 1.92, 95% CI: 0.66–5.58), suggesting that these analyses were statistically underpowered. These findings should be interpreted with caution and validated in larger or pooled datasets. In conclusion, in patients with endometriosis, AC-FET was associated with an increased risk of threatened abortion, HDP and placenta previa. The additive effect observed for threatened abortion underscores the need for careful monitoring during early pregnancy in this population and supports considering NC-FET for those at high risk of miscarriage.

Endometriosis is defined as the presence of an endometrium-like tissue outside the uterus [ 1 ]. The estimated prevalence of endometriosis is 10% among women of reproductive age and 30–50% among those with pelvic pain or infertility [ 2 ]. The pathogenic mechanisms related to endometriosis and infertility include mechanical factors, such as pelvic adhesions and anatomical distortions, as well as hormonal disturbances caused by progesterone resistance and estrogen predominance, which affect endometrial receptivity. Additionally, increased reactive oxygen species and inflammation-mediated damage due to endometrioma lead to a reduction in the ovarian reserve [ 3 ]. Many women with endometriosis who experience infertility require assisted reproductive technology to achieve pregnancy [ 4 ]. The age of marriage has been rising in the general population, leading to a global increase in the use of ART, particularly frozen embryo transfer (FET). This trend has heightened the interest in obstetric and perinatal complications associated with different endometrial preparation methods for FET, resulting in a growing body of research on this topic [ 5 – 8 ]. According to national cohort studies, endometriosis is known to elevate the risk of various obstetric and perinatal complications, including placenta previa, postpartum hemorrhage (PPH), placental abruption, premature rupture of membranes (PROM), and low birth weight according to national cohort studies [ 9 – 11 ]. In line with these societal trends, recent studies have examined pregnancy and obstetric outcomes according to FET protocols in patients with endometriosis ([ 12 ]– [ 13 ]). However, these studies have been limited to populations with endometriosis, and it remains unclear whether adverse outcomes are primarily attributable to endometriosis itself or to the endometrial preparation methods used. Therefore, this study aimed to compare pregnancy and obstetric outcomes of singleton deliveries following FET using different endometrial preparation methods in patients with and without endometriosis, utilizing a national cohort database from the Republic of Korea, to identify the optimal preparation method for patients with endometriosis and to determine whether endometriosis independently affects these outcomes within the setting of FET.

Supplementary Material 1 Supplementary Material 1