Effectiveness and Safety of Korean Medicine in Treating Female Infertility: A Prospective Multicenter Observational Study.

Infertility is generally defined as the inability to conceive after 12 months of unprotected intercourse. 1 For individuals aged 35 or older, evaluation and treatment are recommended after six months of trying, considering medical history and physical findings. 2 Globally, an estimated 48 million couples experience infertility, 3 and in Korea, the number of individuals seeking infertility treatment was reported to be 238,601 in 2022. 4 In 2006, the Korean government launched a financial support program for infertility treatment, gradually expanding eligibility criteria and the number of supported cycles. However, despite these efforts, the fertility rate continues to decline, raising concerns about the adequacy of current policy measures. 5 Improving pregnancy outcomes and enhancing the effectiveness of infertility treatments are crucial for addressing the declining birth rate. Numerous international studies have explored the potential benefits of Korean Medicine (KM), including acupuncture and herbal medicine, for the treatment of infertility. 6–8 However, Korea’s dual medical system, which legally and institutionally separates KM and conventional medicine (CM), creates barriers to effective collaboration. Differences in medical philosophy and limited coordination in patient care pathways further complicate efforts to integrate infertility services. These structural challenges impede the delivery of effective collaborative treatments and restrict opportunities to substantiate the efficacy of KM-based infertility therapies through large-scale research. As a result, most studies on KM-based infertility treatments in Korea have been limited to case reports 9 or retrospective analyses of local government-supported programs. 10 , 11 Randomized controlled trials (RCTs) on KM infertility treatments remain rare due to challenges in study design and ethical considerations related to control groups. While a prospective observational study on women with unexplained infertility has been conducted, 12 , 13 it primarily utilized specific interventions and prescriptions, making it difficult to fully capture the personalized approach of KM infertility care and limiting the generalizability of pregnancy outcomes. To address these challenges, this prospective observational study was conducted. This multicenter study included six KM hospitals and 42 KM clinics across Korea, where standardized medical record forms were employed to ensure consistent and systematic data collection. The study aimed to recruit at least 100 female patients undergoing KM infertility treatment. The primary objective of this study was to investigate the clinical characteristics and treatment patterns of KM infertility care by documenting the therapeutic modalities employed and their clinical courses. The secondary objective was to assess the real-world effectiveness and safety of KM infertility treatments based on the systematically collected clinical data.

Participants who consented to third-party data sharing and secondary use were enrolled in the registry maintained by the NIKOM. Such registries provide reliable real-world clinical insights and facilitate long-term monitoring of treatment effectiveness and safety, 43 making them valuable resources for prospective observational studies on KM infertility care. Future efforts should aim to streamline data collection procedures, define core data variables, and incorporate mobile-based self-reporting systems to support the establishment of a large-scale KM infertility registry. Integrating follow-up data from the NHIS would further enable comprehensive tracking of pregnancy, delivery, and neonatal outcomes. In addition, future studies should explore the optimal timing of KM interventions during IVF cycles, assess their capacity to mitigate ART-related side effects, and validate their clinical effectiveness in larger and more diverse populations. This type of research highlights the importance of establishing a structured system that facilitates effective collaboration between KM and CM to enhance patient-centered infertility care. Such initiatives may strengthen the scientific evidence base for KM infertility treatment and support the development of a provider-led integrative care model. Ultimately, these efforts could inform evidence-based national policies and improve access to comprehensive infertility services in response to Korea’s persistent low birth rate.

During the study period, 106 participants provided written informed consent and underwent screening procedures. Among them, four were excluded during screening and 102 participants were enrolled in the study. All enrolled participants received KM treatments, with data collected according to the study schedule. During the study, 25 participants withdrew, resulting in 77 participants completing the study (CCA). The analysis population (AID) consisted of 96 participants, excluding the four who failed screening and the six who withdrew consent, as shown in Figure 1 . Figure 1 Flowchart of the study. * Participants who withdrew consent were excluded. Abbreviation : F/U, follow up; KM, Korean Medicine. Flowchart of the study. * Participants who withdrew consent were excluded. The 96 participants in the analysis population had a mean age of 36.9 ± 4.1 years (range, 28–44 years), while their spouses had a mean age of 39.3 ± 4.5 years (range, 29–51 years). Among the participants, 63 individuals (65.6%) who received only KM treatments were classified as the KM group, whereas 33 individuals (34.4%) who received both KM treatments and concurrent CM infertility treatments were classified as the KM-CM group. The most common cause of infertility was unexplained infertility, identified in 57 cases (59.4%). Male factor infertility was identified in 20 cases (20.8%). The most frequently observed pattern identification among participants was the Kidney Deficiency type. Detailed data are presented in Table 2 . Table 2 Participant Characteristics Variables Responses Variables Responses Demographic characteristics, mean± SD History of infertility treatment, N (%) Age (years) 36.9 ± 4.1 KM infertility treatment Spouse age (years) 39.3 ± 4.5  Yes 32 (33.3) Duration of marriage (months) 45.2 ± 30.8  No 64 (66.7) Duration of attempting pregnancy (months) 27.6 ± 21.1 CM infertility treatment Obstetric history, N (%)  Yes 66 (68.8) Term birth  No 30 (31.2)  0 89 (92.7) Types of CM infertility treatments  1 6 (6.3) Experienced a , N (%, Number of trials)  Missing 1 (1.0) Ovulation induction (including clomiphene) 29 (30.2, 2.8 ± 1.4) Preterm birth IUI 22 (22.9, 1.9 ± 1)  0 95 (99.0) IUI with ovarian stimulation 10 (10.4, 2.5 ± 1.4)  Missing 1 (1.0) IVF 31 (32.3, 3 ± 2.5) Abortion IVF/ICSI 15 (15.6, 2.6 ± 2.8)  0 59 (61.5) Concurrent CM infertility treatments, N (%)  1 19 (19.8) No (KM group) 63 (65.6)  2 13 (13.5) Yes (KM-CM group) 33 (34.4)  3 4 (4.2) Types of concurrent CM infertility  Missing 1 (1.0) Treatments a , N (%) Living children Ovulation induction 9 (9.4)  0 89 (92.7) IUI 4 (4.2)  1 6 (6.3) IUI with ovarian stimulation 2 (2.1)  Missing 1 (1.0) IVF 15 (15.6) Medical history, N (%) IVF/ICSI 5 (5.2) No 65 (67.7) Infertility cause a , N (%) Yes 31 (32.3) Unexplained 57 (59.4) Types of medical history a , N (%) Ovulation factors (PCOS) 7 (7.3) Kidney/Genitourinary system 20 (20.8) Ovulation factors (Not PCOS) 6 (6.3) Endocrine system 7 (7.3) Celiac factors (Endometriosis) 5 (5.2) Skin/Mucous membranes 3 (3.1) Celiac factors (Not endometriosis) 3 (3.1) Cardiovascular system 2 (2.1) Tubal factors 5 (5.2) Gastrointestinal/Liver/Biliary system 2 (2.1) Immunological factors 1 (1.0) Nervous/Mental system 2 (2.1) Others 14 (14.6) Respiratory system 1 (1.0) Male factors 20 (20.8) Fracture 1 (1.0) Pattern identification a , N (%) Allergy 1 (1.0) Kidney Deficiency type 65 (67.7) Infertility type, N (%) Blood Deficiency type 37 (38.5) Primary infertility 58 (60.4) Liver Depression type 34 (35.4) Secondary infertility 38 (39.6) Blood Stasis type 21 (21.9) Phlegm-Dampness type 16 (16.7) Notes : Bold text indicates section headers for organizational clarity. a Multiple responses were allowed. Abbreviations : CM, conventional medicine; ICSI, intracytoplasmic sperm injection; IUI, intrauterine injection; IVF, in vitro fertilization; KM, Korean Medicine; PCOS, polycystic ovary syndrome; SD, standard deviation. Participant Characteristics Notes : Bold text indicates section headers for organizational clarity. a Multiple responses were allowed. Abbreviations : CM, conventional medicine; ICSI, intracytoplasmic sperm injection; IUI, intrauterine injection; IVF, in vitro fertilization; KM, Korean Medicine; PCOS, polycystic ovary syndrome; SD, standard deviation. An analysis of KM treatment utilization showed that acupuncture and herbal medicine were the most frequently applied interventions, received by 91 participants (94.8%) and 90 participants (93.8%), respectively. The average duration of treatment was 104.7 days, with an average of 9.9 sessions per participant. Among participants who completed the study (CCA), the average treatment duration was 119.6 days, with an average of 11.5 sessions. Detailed data are presented in Table 3 . Table 3 Utilization, Number of Sessions, and Duration of KM Treatment Interventions Variables AID (N = 96) CCA (N = 77) Participants Treated, N (%) Number of Sessions (Mean ± SD) Participants Treated, N (%) Number of Sessions (Mean ± SD) Utilization of interventions  Total KM treatments 96 (100) 9.9±10.8 77 (100) 11.5±11.4  Herbal medicine 90 (93.8) 4±3.5 74 (96.1) 4.5±3.6  Acupuncture 91 (94.8) 8.5±10.5 72 (93.5) 9.8±11.3  Moxibustion 78 (81.3) 7.7±10.7 61 (79.2) 8.9±11.6  Cupping 46 (47.9) 4.8±9.2 40 (51.9) 5.8±10  Pharmacopuncture 33 (34.4) 3±6.2 28 (36.4) 3.6±6.8  Chuna 21 (21.9) 5.6±9 18 (23.4) 1.9±5.4  Others 61 (63.5) 9.9±10.8 50 (64.9) 6.5±9.7 KM treatment duration (days) 96 104.7±74.4 77 119.6±70.5 Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; KM, Korean Medicine; SD, standard deviation. Utilization, Number of Sessions, and Duration of KM Treatment Interventions Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; KM, Korean Medicine; SD, standard deviation. Other KM treatments utilized for infertility included thermotherapy (eg, infrared therapy), aromatherapy, vaginal steaming therapy, interferential current therapy (ICT), and topical applications. The study analyzed combination patterns of four core KM interventions—acupuncture, herbal medicine, moxibustion, and cupping, as shown in Figure 2 . The most frequently used combination involved all four modalities, applied in 40 participants (41.7%). With the exception of four participants who received only herbal medicine, the vast majority of participants received two or more KM treatments in combination, reflecting the integrative nature of KM practice in infertility care. Figure 2 Combinations of the four most frequently used interventions applied to participants. Abbreviations : Acu, acupuncture; Cup, cupping; H-med, herbal medicine; Mox, moxibustion. Combinations of the four most frequently used interventions applied to participants. The herbal medicines prescribed to participants and their compositions were analyzed. The most frequently prescribed formula was Jogyeongjongok-tang , which was prescribed 162 times across 23 participants. A detailed list of the prescribed herbal medicines and their constituent herbs is provided in Table 4 . Table 4 Prescribed Herbal Medicine and Constituent Medicinal Herbs Herbal Medicine Korean Name (Chinese Name a ) Prescriptions (Times) Participants N (%) Medicinal Herbs Prescriptions (times) Jogyeongjongok-tang (Tiao Jing Zhong Yu Tang) 162 23 (25.6) Angelica sinensis 325 Guibi-tang (Gui Pi Tang) 76 15 (16.7) Paeoniae Radix 303 Yuklinzu (Yu Lin Zhu) 60 10 (11.1) Zingiberis Rhizoma Recens 230 Jeongkyeong-Tang (Ding Jing Tang) 44 1 (1.1) Poria Sclerotium 225 Danggwisayeokgaohsuyusaenggang-tang (Dang Gui Si Ni Jia Wu Zhu Yu Sheng Jiang Tang) 36 3 (3.3) Citri Unshius Pericarpium 208 Jagamcho-tang (Zhi Gan Cao Tang) 30 3 (3.3) Rehmanniae Radix Preparata 205 Onkyung-tang (Wen Jing Tang) 26 7 (7.8) Cnidii Rhizoma 202 Gyejibokryeong-hwan (Gui Zhi Fu Ling Wan) 22 5 (5.6) Cinnamomi Cortex 195 Daeyeoung-jeon (Da Ying Jian) 22 7 (7.8) Ginseng Radix 192 Anjeonyicheon-tang (An Dian Er Tian Tang) 20 8 (8.9) Glycyrrhizae Radix et Rhizoma 191 Onpojongok-tang (Wen Bao Zhong Yu Tang) 20 6 (6.7) Atractylodis Rhizoma Alba 176 Baelanchagsang-bang (Pai Luan Zhe Chuang Fang) 18 5 (5.6) Zizyphi Fructus 163 Notes : a Herbal medicines are named based on the Chinese pronunciation of the traditional Chinese characters. Prescribed Herbal Medicine and Constituent Medicinal Herbs Notes : a Herbal medicines are named based on the Chinese pronunciation of the traditional Chinese characters. The costs of KM infertility treatment were assessed based on total expenses incurred during the treatment period. This included the National Health Insurance Service (NHIS) covered expenses, out-of-pocket payments, and costs for non-reimbursable items. The analysis of KM infertility treatment costs, conducted using both the AID and CCA methods, is presented in Table 5 . Table 5 Cost of Korean Medicine for Infertility Treatment During the Study Period Variables AID (N = 96) CCA (N = 77) N Mean ± SD (₩) N Mean ± SD (₩) Consultation 81 130,930±137,508 75 135,016±141,862 Inspection 61 41,771±48,431 57 43,397±49,469 Acupuncture/ Electroacupuncture 75 232,785±302,897 69 245,380±312,438 Moxibustion 46 56,113±58,071 40 57,191±60,928 Pharmacopuncture 26 238,558±141,880 23 246,196±146,857 Herbal medicine 79 1,502,877± 801,587 73 1,510,548±791,025 Cupping 30 85,775±113,341 29 87,814±114,786 Chuna 3 118,404±104,422 3 118,404±104,423 Other treatment 63 55,406±65,284 58 57,569±66,923 Total 83 1,981,772± 1,153,183 76 2,026,212±1,145,072 Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; SD, standard deviation; ₩, South Korean won. Cost of Korean Medicine for Infertility Treatment During the Study Period Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; SD, standard deviation; ₩, South Korean won. A total of 20 participants achieved clinical pregnancy during the study. The CPR for the 96 participants in the analysis population was 20.8% (95% CI, 13.9–30.0%) based on AID analysis. Excluding dropouts, the CPR for the 77 participants who completed the study was 26.0% (95% CI, 17.5–36.7%) based on CCA analysis. To account for variations in ovarian cycles among participants, the pregnancy rate per menstrual cycle was calculated to objectively reflect ovulation-related pregnancy outcomes. Across the study period, the 96 participants underwent a total of 429 treatment cycles, resulting in a pregnancy rate per cycle of 4.7% (95% CI, 3.0–7.1%) in the AID analysis. Excluding dropouts, the 77 participants completed 364 cycles, yielding a pregnancy rate per cycle of 5.5% (95% CI, 3.6–8.3%) in the CCA analysis. Of the 96 participants, 57 received more than 3 months of KM treatment, and 9 of them achieved pregnancy, resulting in a CPR of 15.8% (95% CI, 8.5–27.4%) in the AID analysis. Among the 77 participants who completed the study, 53 received treatment for more than 3 months, with 8 achieving pregnancy, resulting in a CPR of 15.1% (95% CI, 7.9–27.0%) in the CCA analysis. Among the 20 participants who achieved pregnancy, 14 (70%) successfully maintained their pregnancy beyond 12 weeks, while 6 (30%) experienced pregnancy loss. Therefore, the OPR was estimated at 70% (95% CI, 48.1–85.5%). The severity of dysmenorrhea, PMS, and infertility-related stress was assessed using the NRS score. As the pre- and post-treatment scores for all measures did not follow a normal distribution, the Wilcoxon signed-rank test was employed. Both the AID and CCA analyses demonstrated a statistically significant reduction in the severity of dysmenorrhea and PMS following KM treatment (p 0.05). Detailed results are provided in Table 6 . Table 6 Severity of Dysmenorrhea, Premenstrual Syndrome, Infertility-Related Stress, and Sexual Intercourse Frequency Before and After Korean Medicine Treatment Variables AID (N = 96) CCA (N = 77) N Before Treatment (Mean ± SD) After Treatment (Mean ± SD) p-value N Before Treatment (Mean ± SD) After Treatment (Mean ± SD) p-value Dysmenorrhea (NRS) 95 3.4 ± 2.6 2.3 ± 2.4 <0.0001 77 3.3 ± 2.6 2.0 ± 2.3 <0.0001 PMS (NRS) 93 2.0 ± 2.4 1.6 ± 2.2 0.019 76 1.8 ± 2.2 1.3 ± 1.8 0.022 Infertility stress (NRS) 80 5.6 ± 2.5 5.3 ± 2.7 0.34 76 5.6 ± 2.5 5.3 ± 2.6 0.34 Sexual intercourse (times) 81 3.0 ± 2.3 3.0 ± 2.4 0.983 76 3.1 ± 2.2 3.1 ± 2.4 0.898 Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; NRS, numeric rating scale; PMS, premenstrual syndrome; SD, standard deviation. Severity of Dysmenorrhea, Premenstrual Syndrome, Infertility-Related Stress, and Sexual Intercourse Frequency Before and After Korean Medicine Treatment Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; NRS, numeric rating scale; PMS, premenstrual syndrome; SD, standard deviation. The EQ-5D scores before and after KM treatment were analyzed using the McNemar–Bowker test. The EQ-5D assessed five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The analysis revealed no statistically significant differences in any of the dimensions before and after treatment (p > 0.05). Detailed results are provided in Table 7 . Table 7 Health Evaluation Scores (EQ-5D) Before and After Korean Medicine Treatment Mobility After treatment Before treatment 1 2 3 1 66 0 0 2 0 0 0 3 0 0 0 Self care After treatment Before treatment 1 2 3 1 66 0 0 2 0 0 0 3 0 0 0 Usual activities After treatment Before treatment 1 2 3 1 63 3 0 2 0 0 0 3 0 0 0 Pain/Discomfort After treatment Before treatment 1 2 3 1 52 7 0 2 4 3 0 3 0 0 0 Anxiety/Depression After treatment Before treatment 1 2 3 1 66 0 0 2 0 0 0 3 0 0 0 Health Evaluation Scores (EQ-5D) Before and After Korean Medicine Treatment Among the 14 participants who maintained pregnancy beyond 12 weeks, 13 delivered at full term, while one participant experienced a second-trimester miscarriage. All 13 full-term deliveries resulted in live births. The live birth rate (LBR) was 13.5% (95% CI, 8.1–21.8%) based on the 96 participants in the analysis population (AID) and 16.9% (95% CI, 10.1–26.8%) based on the 77 participants who completed the study (CCA). The average gestational age at delivery was 38.2 ± 1.2 weeks. Of the 13 deliveries, 9 (69.2%) were cesarean sections, and 4 (30.8%) were vaginal deliveries. No cases of multiple births or congenital anomalies were reported. The pregnancy and delivery outcomes of this study are summarized in Table 8 , aligned with the core outcome measures for infertility research. 15 Table 8 Pregnancy and Birth Outcomes Based on Core Outcome Set in Infertility Research Variables N AID (CCA) % AID (CCA) 95% CI Intrauterine pregnancy  Singleton 20 20.8 (26.0) 13.9–30.0 (17.5–36.7)  Multiple pregnancy 0 0 0 Pregnancy loss  Ectopic pregnancy 0 0 0  Miscarriage 7 35 18.1–56.7  Stillbirth and termination of pregnancy 0 0 0 Live birth 13 13.5 (16.9) 8.1–21.8 (10.1–26.8) Neonatal mortality 0 0 0 Major congenital anomaly 0 0 0 Gestational age at delivery (weeks) 38.2±1.2 Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; CI, confidence intervals. Pregnancy and Birth Outcomes Based on Core Outcome Set in Infertility Research Abbreviations : AID, analysis including dropouts; CCA, complete case analysis; CI, confidence intervals. An additional analysis was performed on the 96 participants to compare the outcomes between the KM and KM-CM groups, as illustrated in Figure 3 . The normality of continuous variables was assessed using the Shapiro–Wilk test. The KM group met the assumption of normality (p = 0.096), whereas the KM-CM group did not (p = 0.010). Consequently, the Mann–Whitney U -test was employed to compare mean age between the two groups. The KM group (N = 63) had a mean age of 36.3 ± 4 years, whereas the KM-CM group (N = 33) had a mean age of 38 ± 4.2 years. Although the KM-CM group tended to be older, the difference in age between the two groups was not statistically significant (Mann–Whitney U = 1284.0, p = 0.0589). In addition, there were no significant differences between the two groups regarding the types and causes of infertility (p > 0.05). Figure 3 Types and causes of infertility and pregnancy outcomes in the KM and KM-CM groups. Abbreviations : CM, conventional medicine; KM, Korean Medicine; PCOS, polycystic ovary syndrome. Types and causes of infertility and pregnancy outcomes in the KM and KM-CM groups. In terms of pregnancy and delivery outcomes, the KM group had a CPR of 19.0% (95% CI, 11.3–30.4%), an OPR of 75% (95% CI, 46.8–91.1%), and an LBR of 12.7% (95% CI, 6.6–23.1%). In the KM-CM group, the CPR was 24.2% (95% CI, 12.8–41.0%), the OPR was 62.5% (95% CI, 30.6–86.3%), and the LBR was 15.2% (95% CI, 6.7–30.9%). However, none of these differences were statistically significant, as determined by Fisher’s exact test (p > 0.05). An additional analysis was performed on 96 participants to examine differences according to the type of KM medical institution they visited. Among those treated at KM clinics (N = 55), 76.4% received KM-only treatment, compared to 51.2% among those treated at KM hospitals (N = 41), showing a statistically significant difference ( χ² -test, p = 0.010). The CPR was 20.0% (95% CI, 11.6–32.4%) for participants treated at KM clinics and 22.0% (95% CI, 12.0–36.7%) for those at KM hospitals. However, no significant difference in CPR was observed between the two groups based on Fisher’s exact test (p = 1.000). Detailed results are presented in Table 9 . Table 9 Treatment Groups and Pregnancy Rates by Medical Institutions Variables KM Clinics (N=55) KM Hospitals (N=41) p-value Treatment groups  KM group 42 (76.4%) 21 (51.2%) 0.010  KM-CM group 13 (23.6%) 20 (48.8%) Clinical pregnancy  Pregnant 11 (20.0%) 9 (22.0%) 1.000 a  Not pregnant 44 (80.0%) 32 (78.0%) Notes : a Fisher’s exact test was used instead of the chi-square test because of the small sample size and the low expected frequency in some cells. Abbreviations : CM, conventional medicine; KM, Korean Medicine. Treatment Groups and Pregnancy Rates by Medical Institutions Notes : a Fisher’s exact test was used instead of the chi-square test because of the small sample size and the low expected frequency in some cells. Abbreviations : CM, conventional medicine; KM, Korean Medicine. Safety data were analyzed for 102 participants, excluding four who failed screening. Among them, three participants (2.9%, 95% CI, 1.0–8.3%) experienced AEs after initiating KM infertility treatment, with a total of five AEs recorded. No SAEs were reported (0.0%, 95% CI, 0.0–0.0%). Specifically, one participant reported two episodes of diarrhea and an ovarian cyst, while the other two participants experienced acute urticaria and COVID-19 infection, respectively. Detailed information is provided in Table 10 . Table 10 Adverse Events AEs Continuation of the Study Severity Causal Relation Diarrhea Continuation Mild Considered related Diarrhea Continuation Mild Considered related Ovarian cyst Discontinuation Mild Considered unrelated Acute urticaria Discontinuation Mild Considered related COVID-19 Continuation Mild Definitely unrelated Abbreviation : AEs, adverse events. Adverse Events Abbreviation : AEs, adverse events. Overall AE incidence was 4.9% (95% CI, 2.1–11.0%), the dropout rate due to AEs was 2.0% (95% CI, 0.5–6.9%), and the incidence of AEs related to KM treatment was 2.9% (95% CI, 1.0–8.3%).

This prospective multicenter observational study was conducted to evaluate the real-world application of KM infertility care. A total of six university-affiliated KM hospitals and 42 KM clinics across the country participated, and the study aimed to enroll at least 100 female patients undergoing KM treatment for infertility. The target sample size was based on previous studies reporting a clinical pregnancy rate (CPR) of approximately 20–25%, 14 which was considered sufficient to estimate CPR with a 95% confidence level and acceptable precision (±9%) for an observational study. The study was conducted between October 18, 2021, and January 23, 2024, in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to the initiation of the study. Participants who agreed to data sharing and secondary use were registered in a registry maintained by the National Institute for Korean Medicine Development (NIKOM). The study protocol was registered with the Korean Clinical Trial Registry (KCT0006763), and full methodological details are available in the published protocol. (1) Women aged 20–44 years diagnosed with infertility, defined as the inability to conceive after one year of unprotected intercourse (or six months for women aged 35 years or older). 1 , 2 (1) Women aged 20–44 years diagnosed with infertility, defined as the inability to conceive after one year of unprotected intercourse (or six months for women aged 35 years or older). 1 , 2 This criterion also included women whose infertility was associated with tubal or uterine factors, or whose partners had male factor infertility (eg, abnormal semen analysis). (2) Participants who agreed to the study objectives and provided consent for the use of their clinical data for analysis. (2) Participants who agreed to the study objectives and provided consent for the use of their clinical data for analysis. (1) Individuals who visited KM institutions for consultations but did not receive KM treatments. (2) Individuals with systemic or mental health conditions that could interfere with the study, as determined by the investigator. Examples include malignant tumors, moderate to severe heart, liver, or kidney disease, schizophrenia, substance abuse or dependence, and epilepsy. (1) Individuals who visited KM institutions for consultations but did not receive KM treatments. (2) Individuals with systemic or mental health conditions that could interfere with the study, as determined by the investigator. Examples include malignant tumors, moderate to severe heart, liver, or kidney disease, schizophrenia, substance abuse or dependence, and epilepsy. Participant information was collected according to the schedule outlined in Table 1 . For participants who became pregnant during the study, additional data were gathered at specified intervals. No additional treatment procedures were conducted beyond those required for observational data collection. KM practitioners provided treatment using various KM interventions, with treatment methods and herbal medicine dosages being determined according to standard clinical practice and adjusted based on individual patient conditions. As a result, there was variability in treatment timing, dosage, and intervention schedules among participants. Data on the concomitant use of CM drugs and treatments were also recorded. Table 1 Trial Schedule Variables Screening Visit 1 Interim Visit After 3 Months Last Day Pregnancy Confirmation a IUP 12 Weeks a After Delivery a Informed consent form ● Registration ● Confirm inclusion criteria ● Vital signs ● Demographics and medical history ● Check medication changes ● ● ● ● ● ● Check treatment history ● ● ● ● ● Check pregnancy ● ● ● ● Check menstrual history ● ● ● ● Assess sexual intercourse frequency ● ● ● Assess infertility stress degree ● ● ● Check EQ-5D score ● ● ● Check adverse event ● ● ● ● ● Check pattern identification ● Check treatment methods ● ● ● ● Assess costs ● ● Check pregnancy maintenance ● Check delivery ● Notes : ● indicates variables that were measured or documented at the corresponding visit. a Collected only for participants who became pregnant during the study period. Abbreviations : EQ-5D, EuroQol-5 Dimension; IUP, intrauterine pregnancy. Trial Schedule Notes : ● indicates variables that were measured or documented at the corresponding visit. a Collected only for participants who became pregnant during the study period. Abbreviations : EQ-5D, EuroQol-5 Dimension; IUP, intrauterine pregnancy. The collected and assessed items included: (1) Participant information: Demographic data, medical and medication history, obstetric history, infertility treatment history, causes of infertility (as identified through prior clinical evaluations), Numerical Rating Scale (NRS) scores for infertility-related stress, and frequency of sexual intercourse. (2) Clinical records from practitioners: Details of KM interventions, including herbal medicine (prescription names and constituent medicinal herbs), acupuncture, pharmacopuncture, electroacupuncture, auricular acupuncture, moxibustion, and Chuna therapy. (3) Pregnancy-related findings and clinical course: Pregnancy status (intrauterine pregnancy confirmed by ultrasound), multiple pregnancies (type and number of live births), pregnancy maintenance (including ectopic pregnancy, miscarriage, stillbirth, and pregnancy loss), delivery status (gestational age, delivery method, and reasons for preterm delivery, if applicable), live birth outcomes (confirmation of live birth or stillbirth, with reasons for stillbirth, if applicable), congenital anomalies (type and details, if any), concomitant CM medications and treatments, menstrual history, severity of dysmenorrhea and premenstrual syndrome (PMS) (assessed using the NRS), health-related quality of life (EuroQol-5 Dimension, EQ-5D), frequency of sexual intercourse, and adverse events. (4) Treatment costs: Total costs of KM infertility interventions, including reimbursable items (covered by National Health Insurance and patient co-payments) and non-reimbursable items. (5) Study withdrawal: Date and reason for withdrawal. (1) Participant information: Demographic data, medical and medication history, obstetric history, infertility treatment history, causes of infertility (as identified through prior clinical evaluations), Numerical Rating Scale (NRS) scores for infertility-related stress, and frequency of sexual intercourse. (2) Clinical records from practitioners: Details of KM interventions, including herbal medicine (prescription names and constituent medicinal herbs), acupuncture, pharmacopuncture, electroacupuncture, auricular acupuncture, moxibustion, and Chuna therapy. (3) Pregnancy-related findings and clinical course: Pregnancy status (intrauterine pregnancy confirmed by ultrasound), multiple pregnancies (type and number of live births), pregnancy maintenance (including ectopic pregnancy, miscarriage, stillbirth, and pregnancy loss), delivery status (gestational age, delivery method, and reasons for preterm delivery, if applicable), live birth outcomes (confirmation of live birth or stillbirth, with reasons for stillbirth, if applicable), congenital anomalies (type and details, if any), concomitant CM medications and treatments, menstrual history, severity of dysmenorrhea and premenstrual syndrome (PMS) (assessed using the NRS), health-related quality of life (EuroQol-5 Dimension, EQ-5D), frequency of sexual intercourse, and adverse events. (4) Treatment costs: Total costs of KM infertility interventions, including reimbursable items (covered by National Health Insurance and patient co-payments) and non-reimbursable items. (5) Study withdrawal: Date and reason for withdrawal. A descriptive analysis was conducted on age, causes of infertility (including spousal factors), types of interventions used (including CM treatments), history of medical interventions, and other demographic details of participants undergoing KM infertility treatment. Data on therapeutic interventions, including treatment duration and frequency of each intervention, were subjected to analyzed. The names and compositions of prescribed herbal medicines were also examined. A descriptive analysis was performed on the costs associated with KM infertility treatment for participants. For participants who achieved pregnancy following KM infertility treatment, a descriptive analysis was conducted on gestational age at delivery, delivery method, live birth incidence, occurrence of multiple pregnancies, and presence of congenital anomalies. - CPR: (Total number of clinical pregnancies / Total number of participants) × 100 (%). A clinical pregnancy was defined as one in which a fetal heartbeat was confirmed by ultrasound at approximately 6 weeks of pregnancy. - Pregnancy rate per cycle: (Total number of clinical pregnancies / Total number of treatment cycles [menstrual cycles]) × 100 (%). - CPR in participants treated for more than 3 months = (Number of pregnancies among participants treated for more than 3 months / Total number of participants treated for more than 3 months) × 100 (%). - CPR: (Total number of clinical pregnancies / Total number of participants) × 100 (%). A clinical pregnancy was defined as one in which a fetal heartbeat was confirmed by ultrasound at approximately 6 weeks of pregnancy. - Pregnancy rate per cycle: (Total number of clinical pregnancies / Total number of treatment cycles [menstrual cycles]) × 100 (%). - CPR in participants treated for more than 3 months = (Number of pregnancies among participants treated for more than 3 months / Total number of participants treated for more than 3 months) × 100 (%). - 12-week pregnancy maintenance rate (ongoing pregnancy rate, OPR). - Symptom changes related to dysmenorrhea and PMS. - Changes in NRS score for infertility-related stress. - EQ-5D score. - 12-week pregnancy maintenance rate (ongoing pregnancy rate, OPR). - Symptom changes related to dysmenorrhea and PMS. - Changes in NRS score for infertility-related stress. - EQ-5D score. Safety evaluations were conducted for all adverse events (AEs) reported during the study period. The analysis included the incidence rates of AEs, serious adverse events (SAEs), AEs leading to participant dropout, and those associated with KM treatments. AEs were recorded at each visit based on researcher observations and participant-reported symptoms. To reflect real-world clinical scenarios, the study primarily employed the Analysis Including Dropouts (AID) approach. To address the potential impact of high dropout rates on result reliability, an additional Complete Case Analysis (CCA), which excluded dropouts, was conducted for effectiveness evaluations and the assessment of KM treatment duration and costs. Continuous variables were summarized as mean ± standard deviation (SD), while categorical variables were expressed as frequencies and percentages, along with their 95% confidence intervals (CI) where appropriate. The normality of continuous variables was assessed using the Shapiro–Wilk test. For variables that satisfied the assumption of normality, paired t-tests were used to compare pre- and post-treatment outcomes. When normality was not satisfied, the Wilcoxon signed-rank test was applied. Student’s t-tests or Mann–Whitney U -tests were used to compare effectiveness indicators across participant characteristics or treatment interventions, based on data distribution. For comparisons of categorical variables, the chi-square test was used when expected frequencies were sufficient, and Fisher’s exact test was applied when sample sizes were small or expected frequencies were less than 5. A p-value less than 0.05 was considered statistically significant. The Last Observation Carried Forward (LOCF) method was applied to impute missing data for the final visit regarding NRS scores for dysmenorrhea and PMS severity, which were assessed at each visit. For infertility-related stress, frequency of sexual intercourse, and EQ-5D, evaluated only at the first and last visits, participants with missing data were excluded from the analysis.

This prospective multicenter observational study investigated the current status, clinical course, and outcomes of KM infertility treatments in real-world settings. It also examined the clinical effectiveness and safety of KM treatments for female infertility. Future research should prioritize the expansion of registry-based prospective studies to generate higher-quality evidence on the effectiveness and safety of KM infertility treatments.

This study reflects the real-world application of KM in the management of infertility in South Korea, amid growing national concern over declining birth rates, which has prompted greater interest in integrative approaches. The average age of participants was 36.9 years, with their spouses averaging 39.3 years, suggesting a trend toward older reproductive age groups compared to previous KM infertility studies. 14 Advanced age is a well-recognized risk factor for infertility and miscarriage, particularly in women over 35 and men over 40. 16 , 17 Age-related reproductive decline—including diminished ovarian reserve, 18 impaired endometrial receptivity, 19 and reduced frequency of sexual intercourse (reported at an average of three times per menstrual cycle)— highlight the need for a comprehensive treatment strategy that supports both physiological and behavioral aspects of fertility. Unexplained infertility, accounting for 59.4% of participants, represents a key focus of KM treatment because of its potential for natural conception. Studies have shown that for patients with moderate prognoses, intrauterine insemination (IUI) does not offer a significant advantage over expectant management within six months. 20 , 21 For women with favorable prognoses, KM treatment serves as a less invasive therapeutic option that may support natural conception and preserve ovarian function. Among the 96 participants, including dropouts, the CPR was 20.8%, with an OPR of 70% and an LBR of 13.5%. When excluding dropouts, the CPR and LBR increased to 26.0% and 16.9%, respectively. These outcomes were slightly lower than the 28.4% pregnancy rate per in vitro fertilization (IVF) cycle reported in 2019 under the government subsidy program. 22 However, as the IVF pregnancy rate included 0.9% ectopic pregnancies and 20% multiple pregnancies, direct comparisons should be interpreted with caution. Notably, no multiple births, congenital anomalies, or SAEs were reported among participants who achieved pregnancy through KM treatment, supporting its safety. By using pregnancy rates per menstrual cycle, this study provides a cycle-adjusted and more objective evaluation of treatment outcomes. This method allows for more accurate comparisons with assisted reproductive technology (ART) outcomes, particularly in settings where treatment cycles are irregular or frequently canceled. Accumulating evidence supports the clinical efficacy of KM interventions for female infertility. Acupuncture, administered to 94.8% of participants in this study, has been shown to regulate the hypothalamic-pituitary-ovarian axis, restore hormonal balance, improve ovarian blood flow, reduce granulosa cell apoptosis, and enhance endometrial receptivity. 23–25 It may also alleviate emotional distress, such as anxiety and depression, which may contribute to improved treatment adherence. 26 Herbal medicine, administered to 93.8% of participants, has shown improved pregnancy outcomes in comparison with pharmaceutical or ART treatments. 27 Its benefits extend to cases of anovulation, endometriosis, and tubal obstruction. 28–31 Preclinical studies indicate that herbal medicine may inhibit granulosa cell apoptosis, support luteal function, 32 and enhance oocyte responsiveness during IVF, leading to improved live birth rates. 33 The most frequently prescribed formula in this study, Jogyeongjongok-tang , is widely used to treat menstrual irregularities and infertility related to mental stress. 34 Surveys of KM physicians have identified it as the most preferred herbal prescription for infertility treatment, 35 and it has been incorporated into government-supported infertility programs due to its effectiveness in improving CPR and OPR. 36 Although national support for ART continues to expand, treatment discontinuation remains a concern, with global dropout rates reaching 36.2% and approximately 30% reported in Korea. 37 , 38 Among ART patients, 40.9% reported psychological distress and isolation, while 26.6% experienced physical discomfort and pain. 37 KM interventions may offer synergistic benefits when combined with ART, including improved pregnancy outcomes, 39 , 40 reduced treatment-related discomfort, 41 and psychological support. 42 Expanding access to KM infertility treatments represents more than an alternative option; it may encourage women to continue pursuing conception, particularly those who have discontinued ART due to treatment failures or physical and emotional challenges.

This study has several limitations that warrant consideration. First, as an observational study without a control group, causal inference is limited. The results should be interpreted as representative of real-world clinical practice. Second, the study was conducted during the COVID-19 pandemic, likely contributing to reduced visits to KM institutions and limited participant recruitment. A total of 106 participants were enrolled, and the dropout rate was 23.6%. Although both AID and CCA approaches were employed to mitigate the impact of attrition, the possibility of selection bias cannot be entirely excluded. Third, the study included participants with heterogeneous infertility etiologies, such as male factor and tubal factor infertility. However, subgroup analyses could not be performed due to the small number of cases in each category. In addition, treatment protocols were not standardized across sites, as KM interventions were delivered according to routine clinical practice. While this heterogeneity reflects real-world conditions, it may introduce variability in treatment outcomes. Despite these limitations, the study has several notable strengths. It included a wide range of KM clinics and hospitals nationwide, enhancing the generalizability of findings and minimizing institutional bias. Unlike studies based solely on health insurance claims data, this research included both reimbursable and non-reimbursable treatments, such as herbal medicine and pharmacopuncture, providing a more comprehensive view of current KM infertility practices. Moreover, this study systematically reported six of the seven core outcome measures for infertility research, 15 excluding only neonatal birth weight, ensuring a comprehensive assessment of pregnancy and delivery outcomes.