Trends and Determinants of Acute Tocolysis Utilization in Japan: A Nationwide Retrospective Cohort Study

Trends and Determinants of Acute Tocolysis Utilization in Japan: A Nationwide Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Trends and Determinants of Acute Tocolysis Utilization in Japan: A Nationwide Retrospective Cohort Study Mikayo Toba, Rie Oi, Mutsuko Moriwaki, Masayuki Kakehashi, Ayako Fudono, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7777057/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Preterm birth remains a leading cause of neonatal mortality worldwide. While Japan has exceptionally low perinatal and neonatal mortality rates, clinical practice for preterm labor often involves maintenance tocolysis (MT) with ritodrine, which differs from international guidelines recommending acute tocolysis (AT) for up to 48 hours. To evaluate the current status of tocolytic practices in Japan, we investigated nationwide trends in the shift from MT to AT use and identify factors associated with the utilization of AT. Methods: This retrospective cohort study analyzed data from 156,356 pregnant women admitted to 720 institutions between April 2012 and March 2023 who received ritodrine infusion for preterm labor. Annual trends in AT utilization rates were examined, and logistic regression analysis was performed to identify factors associated with AT. Factors associated with AT use, including hospital characteristics, regional differences, and maternal obstetric complications, were explored. Results: The rate of AT utilization increased from 15.73% to 23.74% over the 11-year period, but variation among hospitals widened. University hospitals (adjusted odds ratio [aOR] = 1.16, p < 0.001), perinatal centers (aOR = 1.12, p < 0.001), preterm premature rupture of membranes (aOR = 3.18, p < 0.001), and pregnancy-induced hypertension (aOR = 1.52, p < 0.001) were associated with AT, while concomitant use of magnesium sulfate hydrate (aOR = 0.91, p < 0.001), multiple fetuses (aOR = 0.64, p < 0.001), and placenta previa (aOR = 0.67, p < 0.001) were negatively associated with AT utilization. Conclusion: While the rate of AT utilization has increased over time, differences in utilization exist between facilities, suggesting that choice of AT is influenced by multiple factors, including the perinatal medical system, maternal obstetric complications, and regional characteristics. Further discussion and research are needed to optimize treatment strategies to maximize maternal and fetal safety and improve outcomes. Trial registration: Not applicable. preterm labor ritodrine acute tocolysis maintenance tocolysis maternal adverse events Figures Figure 1 Figure 2 Figure 3 Plain English summary Preterm birth, when a baby is born before 37 weeks of pregnancy, is a leading cause of newborn death worldwide. Given the risk of adverse events for both mother and baby, most international guidelines recommend limiting the use of tocolytic agents to a maximum of 48 hours (acute tocolysis: AT) to allow time for steroid administration for fetal lung maturation and for the mother to return to the perinatal center. Japan has one of the lowest rates of premature birth, neonatal death, and infant death in the world. Tocolytic therapy in Japan is often continued for more than 48 hours (maintenance tocolysis:MT), which differs from many international guidelines. We studied over 156,000 pregnant women in Japan who were given ritodrine to stop preterm labor between 2012 and 2023. We found that the utilization of acute tocolysis gradually increased over time, rising from approximately 16% to 24%. Although the use of AT has increased in university hospitals and large perinatal centers, some facilities are not actively utilizing AT. Differences in regions, types of hospitals, and the maternal obstetrics complications influenced whether AT or MT was adopted. Our findings highlight that the choice between AT and MT in Japan is influenced by a complex interplay of factors, including regional factors where the hospital is located, hospital characteristics, and maternal obstetric conditions. This suggests that treatment decisions are being made thoughtfully, taking into account the specific needs of patients and the resources available at each facility. Further research and dialogue are needed to explore how these practices can be optimized to improve outcomes while respecting the unique context of perinatal care in Japan. Background In 2020, an estimated 13.4 million preterm births were reported worldwide, with approximately 1 in 10 newborns being delivered preterm [ 1 ]. Preterm birth is the leading cause of neonatal and under-five mortality [ 2 , 3 ] and increases the risk of severe childhood illnesses [ 4 , 5 ]. Globally, the preterm birth rate has remained relatively stable [ 6 ]. In developed countries, however, the increase in high-risk pregnancies due to maternal aging and assisted reproductive technologies has led to more cases of spontaneous preterm births and medically indicated preterm births, in which early delivery or cesarean section is planned for medical reasons [ 7 , 8 ]. To address this issue, in 2023, the World Health Organization (WHO) recommended the appropriate use of tocolytic agents and the administration of antenatal corticosteroids [ 9 , 10 ]. Among these recommendations, tocolytic agents are recommended in cases of preterm labor to allow time for antenatal corticosteroid administration and ensure sufficient time for maternal transfer to tertiary medical centers equipped with neonatal intensive care units (NICUs) and facilities for preterm infant care. However, the use of tocolytic agents is recommended to be limited to acute tocolysis (AT) for up to 48 hours [ 11 ]. Since the 1980s, betamimetics have been widely used as tocolytic agents worldwide. However, in 2013, the European Medicines Agency concluded that high doses of short-acting betamimetics pose a significant risk of severe cardiovascular side effects for both mother and fetus. Consequently, the agency withdrew approval for oral and suppository formulations and restricted the use of injectable formulations to a maximum of 48 hours [ 12 ]. The World Health Organization (WHO) and the National Institute for Health and Care Excellence recommend the use of nifedipine as a tocolytic agent [ 9 , 13 , 14 ]. The American College of Obstetricians and Gynecologists does not specify a first-line tocolytic agent, but nifedipine and indomethacin are the most commonly used [ 15 ]. In 2020, the preterm birth rate in Japan was 5.48%, and the perinatal mortality and neonatal mortality rates were 3.2 and 0.8 per 1,000 live births, respectively, which are the lowest worldwide, indicating that perinatal healthcare in Japan is at the highest global standard [ 16 – 18 ]. These outcomes are believed to be largely attributed to Japan’s advanced perinatal healthcare system, including the development and functionality of advanced NICUs, the establishment of perinatal medical networks, the widespread availability and high quality of prenatal care, and advancements in techniques for managing complications [ 19 , 20 ]. However, the treatment of preterm labor in Japan is unique globally. First, the tocolytic drugs approved in Japan are limited to beta-agonists such as ritodrine hydrochloride (ritodrine) and magnesium sulfate. Furthermore, both preterm labor cases and threatened preterm labor cases, such as those presenting with uterine contractions alone, are eligible for tocolytic therapy. These drugs are customarily administered for 48 hours or longer as maintenance tocolysis (MT) [ 21 ]. The Japan Society of Obstetrics and Gynecology (JSOG) does not restrict the use of MT [ 22 ]. Following global trends, ritodrine injections decreased by 42.68% in 2022 compared to 2014 [ 23 ]. Caution regarding ritodrine administration is thought to be driving this decline although the actual situation remains unclear [ 24 , 25 ]. The WHO emphasizes the need for consistency between guidelines and clinical protocols at the global, national, regional, and facility levels, as well as the need for clear standards in national guidelines regarding the appropriate use of tocolytic agents and acceptable regimens [ 9 ]. To the best of our knowledge, no study in the literature to date has comprehensively evaluated current tocolytic therapy practices in Japan or explored factors influencing the choice of AT. In this study, we hypothesized that (a) the AT utilization rate has been increasing annually, reflecting a gradual shift toward international practice; (b) patient characteristics, including maternal obstetric complications, differ between those receiving AT and those receiving MT, and (c) hospital perinatal healthcare capabilities and regional differences influence the utilization pattern of tocolytic therapy. To test these hypotheses and provide evidence for evaluating the current status of tocolytic practices in Japan, we aimed to examine nationwide trends in AT utilization rates during the study period and explore factors associated with AT. Methods Study design and setting In this retrospective cohort study, we utilized data from the Diagnosis Procedure Combination (DPC) database. The DPC is a patient categorization system for acute care inpatients in Japan, designed to enhance transparency and visibility in acute-stage medical care. These systems were introduced in 2003 by the Ministry of Health, Labor and Welfare as an inclusive payment model and have been utilized for acute hospital care and distribution of medical resources. This system includes acute care hospitals across Japan who submit data on medical procedures to the government [26]. As of 2023, the DPC database covered 1,761 facilities and 483,459 beds, accounting for 24.9% of general hospitals and 54.5% of beds in Japan. The DPC database collects data such as diagnoses associated with ICD-10 (International Classification of Diseases, 10th Revision) codes as well as patient demographics, including age, sex, existing comorbidities, complications arising after admission, admission and discharge dates, discharge outcomes, destinations after discharge, medications, in-hospital mortality, gestational age at admission, delivery during hospitalization, and details of surgical procedures [27]. Numerous studies on data reliability and clinical epidemiology have been conducted using this database [28–30]. Study population The study participants were pregnant women aged 22⁺0 to 36⁺6 weeks of gestation age who were hospitalized between April 1, 2012, and March 31, 2023, and received ritodrine hydrochloride injection. Patients with unknown gestational age and those transferred from another hospital were excluded, as the treatment status at the previous hospital was unknown. The DPC database collects medication data daily. Among patients who received ritodrine for 3 days, some received it for less than 48 hours (AT) and others for more than 48 hours (MT); therefore, in this study, patients who received ritodrine injections for 2 days or less (within 48 hours) were classified as the AT group, and patients who received ritodrine injections for 4 days or more (more than 48 hours) were classified as the MT group. Variables The variables analyzed in this study included maternal age; the Charlson Comorbidity Index [31, 32]; obstetric diseases—such as preterm premature rupture of membranes (pPROM), hypertensive disorder of pregnancy (HDP), placenta previa, and cervical insufficiency; pregnancy status—specifically gestational age and singleton pregnancy—along with academic hospital status, perinatal medical center designation, hospital region, and fiscal year at admission. The hospitals were categorized into six regions based on geographical location: Hokkaido-Tohoku, Kanto, Chubu, Kansai, Chugoku-Shikoku, and Kyushu-Okinawa. Statistical analysis First, we measured the AT utilization rate on both a patient-by-patient and a hospital-by-hospital basis. We analyzed annual trends in AT utilization rates using the Jonckheere-Terpstra test, to evaluate the presence of monotonic trends over time. Next, patients were divided into groups according to the method of tocolytic agent administration, after which patient and hospital characteristics were summarized using appropriate descriptive statistics. Continuous variables are expressed as means with standard deviations (SD) and were compared between groups using the Mann–Whitney U test. Categorical variables are presented as frequencies with percentages and were compared using the chi-square test. Logistic regression analysis (forced entry method) was then performed with AT utilization as the dependent variable. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). SPSS version 30 (IBM, Chicago, Illinois, USA) was used for all analyses, and the significance level was set at 5% (two-tailed test). Ethical considerations The Institute of Science Tokyo Faculty of Medicine Ethics Review Committee approved this study (approval number: M2000-788; date of approval: December 19, 2023). The committee waived the requirement for informed consent because all personal information was excluded, and de-identified data were provided to the researchers for secondary use. This study was conducted in accordance with the principles of the Declaration of Helsinki. Results Participants During the study period, 191,201 hospitalized patients received ritodrine infusion. The duration of ritodrine administration was assessed for 164,407 patients at 720 hospitals, after excluding patients with an unknown age at admission, patients with an age of 37 weeks or more, or patients with an age of less than 22 weeks, and patients transferred from multiple facilities (Fig. 1 ). The patient-level AT utilization rate increased from 15.08% to 22.26% over the past 11 years. In 2012, 30.68% of patients belonged to the ≥ 28-day group, but this proportion decreased by 7.56% over the past 11 years. The 21–27-day group also decreased by 1.55%, while the 7–13-day and 14–20-day groups remained stable, and the 4–6-day and ≤ 2-day groups increased (Fig. 2 a, Additional file 1). The AT utilization rate by hospitals also showed a monotonically increasing trend, although the variation between hospitals increased over time (Fig. 2 b). We compared patient characteristics between the AT and MT groups among 156,356 patients at 720 facilities, excluding cases in which ritodrine was administered for 3 days (Fig. 1 ). The patient characteristics according to the duration of ritodrine administration are shown in Table 1 . The mean age ± SD of the patients was 31.92 ± 5.48 years in the AT group and 31.76 ± 5.41 years in the MT group (p < 0.001). The mean gestational age at the time of hospitalization was 31.89 ± 4.41 weeks, 29.02 ± 4.40 weeks respectively (p < 0.001). Pregnant women with multiple pregnancies, placenta previa, or cervical insufficiency were more likely to undergo MT, whereas those with pPROM or HDP were more likely to undergo AT. Pregnant women in academic hospitals and perinatal centers were more likely to receive AT. The incidence of antenatal corticosteroid administration was 23.90% for AT and 21.99% for MT (p < 0.001), and the incidence of concomitant use of magnesium sulfate hydrate use was 19.05% for AT and 23.30% for MT (p < 0.001). Table 1 Characteristics of the participants according of ritodrine hydrochloride infusion (N = 156,356) Acute tocolysis *2 N=29,314 Maintenance tocolysis *1 N = 127,042 p *3 Maternal characteristics of admission Age (years) [mean, SD * 4] 31.92 5.48 31.76 5.41 < 0.001 Gestational age (weeks) [mean, SD * 4] 31.89 4.41 29.02 4.40 < 0.001 BMI * 5 (kg/m 2 ) [mean, SD * 4] 23.66 4.35 23.06 3.72 < 0.001 pPROM *6 , n,% 6,607 22.54 10,691 8.42 < 0.001 Multiple pregnancy, n,% 2,362 8.06 15,010 11.81 < 0.001 Placenta previa, n,% 1,692 5.77 10,285 8.10 < 0.001 Cervical insufficiency, n,% 1,172 4.00 8,454 6.65 < 0.001 Gestational diabetes mellitus, n,% 1,352 4.61 7,259 5.71 < 0.001 Hypertensive disorders of pregnancy, n,% 1,639 5.59 4,982 3.92 < 0.001 CCI * 7, ≥ 1, n,% 847 2.89 3,769 2.97 0.481 Institution Academic hospital, n,% 8,442 28.80 34,042 26.80 < 0.001 Perinatal medical center, n,% 11,986 40.89 49,563 39.01 < 0.001 Regions of the hospital Hokkaido-Tohoku, n,% 3,790 12.93 21,578 16.98 < 0.001 Kanto, n,% 7,769 26.50 32,546 25.62 Chubu, n,% 5,477 18.68 26,779 21.08 Kansai, n,% 5,401 18.42 19,748 15.54 Chugoku-Shikoku, n,% 3,764 12.84 16,297 12.83 Kyushu-Okinawa, n,% 3,113 10.62 10,094 7.95 Fiscal year 2012, n,% 1,774 6.05 9,512 7.49 < 0.001 2013, n,% 1,814 6.19 9,825 7.73 2014, n,% 2,429 8.29 12,567 9.89 2015, n,% 2,336 7.97 11,868 9.34 2016, n,% 2,191 7.47 11,290 8.89 2017, n,% 2,057 7.02 10,545 8.30 2018, n,% 2,564 8.75 11,047 8.70 2019, n,% 3,339 11.39 13,387 10.54 2020, n,% 3,503 11.95 12,661 9.97 2021, n,% 3,809 12.99 13,104 10.31 2022, n,% 3,498 11.93 11,236 8.84 Preterm labor management ACS * 8, n,% 7,005 23.90 27,934 21.99 < 0.001 Magnesium sulfate hydrate, n,% 5,583 19.05 29,600 23.30 < 0.001 *1 maintenance tocolysis: ritodrine hydrochloride infusion for exceeding 4 days *2 acute tocolysis: ritodrine hydrochloride infusion for 2 days or less *3 continuous variable: Mann-Whitney U test, discrete variable: χ 2 test *4 standard deviation *5 body mass index *6 preterm premature rupture of membranes *7 Charlson comorbidity index *8 antenatal corticosteroids administration The results of logistic regression analysis of factors influencing the indication for AT are shown in Fig. 3 and Additional file 2. Admission to an academic hospital (aOR: 1.16, 95% CI: 1.12–1.20, p < 0.001), admission to a perinatal center (aOR: 1.12, CI: 1.08–1.15, p < 0.001), and not receiving combination therapy with magnesium sulfate (aOR: 1.10, CI: 1.06–1.15, p < 0.001) were associated with AT use. The association with AT also differed by region, with Kyushu-Okinawa (aOR: 1.79, CI: 1.70–1.90, p < 0.001) showing the strongest association with AT. In addition, compared with that in 2012, the association with AT became stronger over time from 2018 onward (aOR: 1.21, CI: 1.13–1.129, aOR: 1.25, CI: 1.17–1.33, aOR: 1.38, CI: 1.46–1.56, aOR: 1.46, CI: 1.37–1.56, aOR: 1.55, CI: 1.45–1.66, p < 0.001 for each). Among maternal obstetrics complications, pPROM and HDP were strongly associated with AT (aOR: 3.18, CI: 3.06–3.30, aOR: 1.52, CI: 1.43–1.62, p < 0.001 for each), while twins and placenta previa were strongly associated with MT (aOR: 0.64, CI: 0.61–0.67, aOR: 0.67, CI: 0.63–0.71, p < 0.001 for each).The association with AT increased by 1.13 times for each additional week of gestational age. Discussion This nationwide retrospective cohort study is the first to report an 11-year transitional trend in AT and obstetric factors influencing the choice of AT in 156,356 Japanese women who underwent ritodrine infusion for preterm labor. Trends in Acute Tocolysis adoption There is a lack of evidence that continuing tocolytic therapy beyond 48 hours improves neonatal outcomes; therefore, international guidelines and most countries recommend AT [ 7 , 11 , 14 ]. Conversely, adherence to guidelines is reported to be low, and in actual clinical practice, MT after AT and the administration of tocolytic agents for threatened preterm labor are still performed [ 33 – 37 ]. Rousseau et al. identified barriers to guideline adherence, including physicians over 50 years of age, those working in non-university hospitals, and those fearing change [ 35 ]. Additionally, Lee et al. stated that patient opinion plays a major role in obstetricians' decision-making, and that maintenance medications may be prescribed based on the patient's request [ 37 ]. In Japan, ritodrine is the first-line drug for preterm labor, and its use for MT aligns with both domestic guidelines and the package insert [ 22 ]. The JSOG guidelines, revised every three years since 2008, have played a key role in maintaining Japan’s low preterm birth rate, even as maternal aging and the use of assisted reproductive technologies have increased [ 17 ]. In the JSOG guidelines, the global recommendation for AT was first described in 2017. Ritodrine injection use in Japan decreased by 15.3% from 2017 to 2018, reaching 47.4% by 2022 compared to 2017 [ 23 ] ༎Multivariate logistic regression analysis suggested that the association with AT has strengthened over time since 2018, likely due to the influence of guideline descriptions such as this. Furthermore, patients treated at academic hospitals and perinatal centers had a strong association with AT. Many of the committee members who create the guidelines are doctors employed at such facilities, and it is speculated that their frequent exposure to diverse information and publications from Japan and abroad influences their choice of AT. This finding is consistent with the results of Rousseau et al. [ 35 ]. Regional and Institutional Differences in Tocolysis Use This study showed that regional factors are associated with AT use. Previous research has reported that differences in the provision of perinatal medical care between urban and rural areas, as well as availability of obstetricians and gynecologists, can influence medical decision-making and care for mothers and children [ 38 , 39 ]. It is hypothesized that in areas with low population density and vast land area, factors such as long travel distances for obstetric checkups and births, difficulty in transporting the mother due to snow in winter, and availability of obstetricians and pediatricians can influence the choice of MT [ 39 , 40 ]. These findings indicate the importance of selecting the most appropriate treatment for mothers and children based on local healthcare infrastructure and regional conditions. Maternal and Obstetric Conditions Influencing Tocolysis The utilization rate of AT has increased over the past 11 years; however, the preterm birth rate in Japan has remained stable at 5.48%–5.75% for those under 37 weeks of gestation and 0.250%–0.260% for those under 28 weeks of gestation [ 16 ]. This rate is significantly lower than the preterm birth rate in the United States, which ranges from 9.7% to 10.4% [ 41 ]. Enengl et al. identified placenta previa as a specific indication for MT [ 33 ]. Similarly, our findings indicate that placenta previa is more strongly associated with MT. In contrast, conditions such as pPROM and severe hypertensive disorders of pregnancy (HDP), which require careful management due to the potential adverse effects of prolonged gestation on maternal and fetal outcomes, are more strongly associated with AT. Additionally, the early gestational age at admission tends to be more closely linked to MT. These findings suggest that the adoption of AT is not uniform across facilities and that treatment options are often selected based on the maternal condition and clinical context. Importance of Shared Decision-Making in Tocolysis Recommendations from the WHO, American College of Obstetricians and Gynecologists, and National Institute for Health and Care Excellence, among others, stipulate that when administering tocolytic therapy, adequate time and opportunity for shared decision-making should be provided among the pregnant woman, her family, and health care professionals regarding the short- and long-term effects of tocolytic therapy and preterm birth, decisions on resuscitation, limitations to survival, the benefits and harms of AT and MT, and long-term outcomes [ 7 , 11 , 14 ]. Although we could not evaluate these processes in the present study, there remains a lack of evidence to guide appropriate decision-making based on policies, financial resources, geographical environments, and educational factors. Further studies are needed to address these gaps [ 9 ]. Strengths and Limitations of the Study The strength of this study is that it investigated changes over an 11-year period across 720 hospitals, making it highly representative of Japan. In addition, the method of analyzing the actual status of treatment over a long period at multiple facilities using medical fee information, as well as examining factors related to changes in habitual treatment, can be applied to other countries. However, this study has some limitations inherent to perinatal retrospective cohort studies. First, there is the potential for confounding by indication, as patients receiving different durations of tocolysis may differ in terms of severity of preterm labor or other unmeasured clinical factors. Second, the use of an administrative database limits the availability of detailed clinical information, such as severity of the condition, specific treatment indications, and physician decision-making processes. Finally, as an observational study, it is fundamentally unable to establish causal relationships or definitively determine treatment effectiveness. Implications for Clinical Practice and Future Research The findings of this study have important implications for clinical practice and education. By identifying factors that influence the use of AT, this study provides evidence for obstetricians to tailor treatment choices to guidelines and patient conditions. These results may also support shared decision-making. Furthermore, these findings may raise awareness among trainees about unresolved challenges in routinely performed tocolysis. Future prospective studies should compare maternal and neonatal outcomes of long-term versus short-term tocolysis in Japan and include economic evaluations of prolonged therapy. Therefore, to maintain and improve the quality of maternal and child health, further research is needed to establish protocols and evaluate available tocolytic drugs, taking into consideration work style reforms for doctors, shortages of obstetricians and pediatricians, and geographical issues. Conclusions Although the overall AT utilization rate has increased, differences exist in utilization status across facilities, and these gaps are widening. AT use tended to be influenced by factors such as hospital functions, obstetric complications, and regional characteristics. Further studies should explore the optimal tocolytic therapy strategy that minimizes maternal and fetal adverse events while improving neonatal outcomes. Simultaneously, it is important to communicate to pregnant woman, their families, and health care professionals that even with commonly used tocolytic therapies, there is ongoing debate regarding the choice of drug, dosage, and duration of administration. Abbreviations aOR, Adjusted Odds Ratio; AT, Acute Tocolysis; CI, Confidence Interval; DPC, Diagnosis Procedure Combination; GDM, Gestational Diabetes Mellitus; HDP, Hypertensive Disorders of Pregnancy; ICD-10, International Classification of Diseases, 10th Revision; JSOG, Japan Society of Obstetrics and Gynecology; MT, Maintenance Tocolysis; NICU, Neonatal Intensive Care Unit; pPROM, Preterm Premature Rupture of Membranes; SD, Standard Deviation; WHO, World Health Organization Declarations Ethics approval and consent to participate: The Institute of Science Tokyo Faculty of Medicine Ethics Review Committee approved this study (approval number: M2000-788; date of approval: December 19, 2023). The committee waived the requirement for informed consent because all personal information was excluded, and de-identified data were provided to the researchers for secondary use. This study was conducted in accordance with the principles of the Declaration of Helsinki. Consent for publication: Not applicable. Availability of data and materials: The datasets generated and/or analyzed during the current study are not publicly available due to contractual obligations with hospitals but are available from the co-author Kiyohide Fushimi on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: The study was supported by the Sasakawa Health Foundation (2025-07). The funders had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. Authors’ contributions: MT contributed to conceptualization, data curation, investigation, methodology, project administration, and visualization. MM was responsible for data curation, formal analysis, and visualization. RO and AF contributed to conceptualization and methodology. MK performed validation. KF contributed to methodology, provided resources, and NM supervised the study. All authors reviewed the results, contributed to manuscript writing, and approved the final version of the manuscript. Acknowledgments: The authors would like to thank Shunji Shimoda of the National Hospital Organization Headquarters for providing technical support in the extraction and management of patient data. References WHO. Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth. Accessed 6 Jun 2025 Wardlaw T, You D, Hug L, Amouzou A, Newby H [UNICEF report]. UNICEF Report: enormous progress in child survival but greater focus on newborns urgently needed. Reprod Health. 2014;11:82. https://doi.org/10.1186/1742-4755-11-82 Yadav S, Lee B, Kamity R. Neonatal respiratory distress syndrome. Treasure Island, FL: StatPearls Publishing; 2021 Patel RM. Short- and long-term outcomes for extremely preterm infants. Am J Perinatol. 2016;33:318–28. https://doi.org/10.1055/s-0035-1571202 van Dommelen P, Verkerk PH, van Straaten HLM, Dutch Neonatal Intensive Care Unit Neonatal Hearing Screening Working Group. Hearing loss by week of gestation and birth weight in very preterm neonates. J Pediatr. 2015;166:840-3.e1. Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402:1261–71. https://doi.org/10.1016/S0140-6736(23)00878-4 Hoffman MK. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, Number 234. Obstet Gynecol. 2021;138:945–6. https://doi.org/10.1097/AOG.0000000000004612 Tamura N, Hanaoka T, Ito K, Araki A, Miyashita C, Ito S, et al. Different risk factors for very low birth weight, term-small-for-gestational-age, or preterm birth in Japan. Int J Environ Res Public Health. 2018;15:369. https://doi.org/10.3390/ijerph15020369 WHO: recommendations on interventions to improve preterm birth outcomes. https://www.who.int/publications/i/item/9789241508988. Accessed 18 Aug 2025 WHO: recommendations on antenatal corticosteroids for improving preterm birth outcomes. https://www.who.int/publications/i/item/9789240057296 . Accessed 18 Aug 2025 Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2014;2014:CD004352. https://doi.org/10.1002/14651858.CD004352.pub3 European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/referrals/short-acting-beta-agonists. Accessed 18 Aug 2025 Kashanian M, Shirvani S, Sheikhansari N, Javanmanesh F. A comparative study on the efficacy of nifedipine and indomethacin for prevention of preterm birth as monotherapy and combination therapy: a randomized clinical trial. J Matern Fetal Neonatal Med. 2020;33:3215–20. https://doi.org/10.1080/14767058.2019.1570117 National Institute for Health and Care Excellence. Preterm labour and birth NICE guideline. https://www.nice.org.uk/guidance/ng25/resources/preterm-labour-and-birth-pdf-1837333576645. Accessed 18 Aug 2025 Mayer C, Apodaca-Ramos I. Tocolysis. In: Treasure Island, FL: StatPearls Publishing; 2023. StatPearls [Internet]. p. 2025 Jan. PMID: 32965883. e-Stat. Portal site of official statistics of Japan. https://www.e-stat.go.jp/dbview?sid=0003411613. Accessed 20 Sep 2025 Shimano S, Yamada T, Cho K, Sengoku K, Mariya T, Saito T. Changes in preterm and extremely preterm birth rates in Japan after the introduction of obstetrical practice guidelines in 2008. J Obstet Gynaecol Res. 2023;49:2283–94. https://doi.org/10.1111/jog.15722 Sasaki Y, Ishikawa K, Yokoi A, Ikeda T, Sengoku K, Kusuda S, et al. Short- and long-term outcomes of extremely preterm infants in Japan according to outborn/inborn birth status. Pediatr Crit Care Med. 2019;20:963–9. https://doi.org/10.1097/PCC.0000000000002037 Nakamura Y. The role of maternal and child health (MCH) handbook in the era of sustainable development goals (SDGs). J Glob Health Sci. 2019;1:e24. https://doi.org/10.35500/jghs.2019.1.e24 Japan Medical Association. https://www.med.or.jp/english/activities/pdf/2011_04/234_240.pdf. Accessed 18 Aug 2025 Okuda A, Inayama Y, Mizuno K, Takeuchi M, Kawakami K, Mandai M, et al. Long-term vs short-term tocolysis with ritodrine hydrochloride: propensity score-matched analysis. Eur J Obstet Gynecol Reprod Biol. 2023;282:77–82. https://doi.org/10.1016/j.ejogrb.2023.01.011 Japan Society of Obstetrics and Gynecology. Guidelines for obstetrical practice in Japan 2023. Japanese. https://www.jsog.or.jp/activity/pdf/gl_sanka_2023.pdf . Accessed 18 Aug 2025 Ministry of Health, Labour and Welfare. https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000177182.html Accessed 23 Sep 2025 Yoneda SJ. Method to evaluate intravenous maintenance tocolysis for preterm labor. J Obstet Gynaecol Res. 2020;46:2518–25. https://doi.org/10.1111/jog.14484 Yamaji N, Suzuki H, Saito K, Swa T, Namba F, Vogel JP, et al. Tocolytic therapy inhibiting preterm birth in high-risk populations: A systematic review and meta-analysis. Children (Basel). 2023;10:443. https://doi.org/10.3390/children10030443 Matsui H, Jo T, Fushimi K, Yasunaga H. Outcomes after early and delayed rehabilitation for exacerbation of chronic obstructive pulmonary disease: a nationwide retrospective cohort study in Japan. Respir Res. 2017;18:68. https://doi.org/10.1186/s12931-017-0552-7 Hayashida K, Murakami G, Matsuda S, Fushimi K. History and profile of diagnosis procedure combination (DPC): development of a real data collection system for acute inpatient care in Japan. J Epidemiol. 2021;31:1–11. https://doi.org/10.2188/jea.JE20200288 Moriwaki M, Takae A, Toba M, Sasaki M, Ogata Y, Obayashi S, et al. Factors associated with proximal femoral fractures in older adults during hospital stay: a cross-sectional study. BMJ Qual Saf. 2025;34:234–43.. https://doi.org/10.1136/bmjqs-2023-015655 Toba M, Terauchi M, Moriwaki M, Obayashi S, Miyasaka N, Fushimi K. Fractures within 2 years of an obstetric hospitalization: analysis of nationwide administrative data in Japan. J Bone Miner Metab. 2022;40:748–54. https://doi.org/10.1007/s00774-022-01336-4 Moriwaki M, Toba M, Takizawa M, Shimizu H, Tanaka H, Takahashi C, et al. Oral management improves patient outcomes in hematopoietic stem cell transplantation. Int Dent J. 2025;75:100822. https://doi.org/10.1016/j.identj.2025.04.003 Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173:676–82. https://doi.org/10.1093/aje/kwq433 Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83. https://doi.org/10.1016/0021-9681(87)90171-8 Enengl S, Rath W, Kehl S, Oppelt P, Mayr A, Stroemer A, et al. Differences between current clinical practice and evidence-based guideline recommendations regarding tocolysis—an Austria-wide survey. Geburtshilfe Frauenheilkd. 2025;85:47–55. https://doi.org/10.1055/a-2446-1828 Nazifovic E, Husslein H, Lakovschek I, Heinzl F, Wenzel-Schwarz E, Klaritsch P, et al. Differences between evidence-based recommendations and actual clinical practice regarding tocolysis: a prospective multicenter registry study. BMC Pregnancy Childbirth. 2018;18:446. https://doi.org/10.1186/s12884-018-2078-5 Rousseau A, Azria E, Baumann S, Deneux-Tharaux C, Senat MV. Do obstetricians apply the national guidelines? A vignette-based study assessing practices for the prevention of preterm birth. BJOG. 2020;127:467–76. https://doi.org/10.1111/1471-0528.16039 Stelzl P, Kehl S, Oppelt P, Mayr A, Fleckenstein T, Maul H, et al. Maintenance tocolysis, tocolysis in preterm premature rupture of membranes and in cervical cerclage—a Germany-wide survey on the current practice after dissemination of the German guideline. J Perinat Med. 2023;51:775–81. https://doi.org/10.1515/jpm-2022-0572 Lee HH, Yeh CC, Yang ST, Liu CH, Chen YJ, Wang PH. Tocolytic treatment for the prevention of preterm birth from a Taiwanese perspective: a survey of Taiwanese obstetric specialists. Int J Environ Res Public Health. 2022;19:4222. https://doi.org/10.3390/ijerph19074222 Hattori S, Sakata N, Ishimaru M, Tamiya N. Consolidation of the perinatal care system and workload of obstetricians: an ecological study in Japan. Front Glob Womens Health. 2023;4:1030443. https://doi.org/10.3389/fgwh.2023.1030443 Ueda A, Nakakita B, Chigusa Y, Mogami H, Kato G, Ueshima H, et al.Regional disparities in primary Cesarean delivery rates in Japan: the role of obstetrician availability. AJOG Glob Rep. 2024;4:100366. https://doi.org/10.1016/j.xagr.2024.100366 Saito Y, Asakura T, Takashi K, Umazume T, Watari H, Tamakoshi A. Relationship between out-of-facility deliveries and distance and travel time to delivery facilities in Hokkaido, Japan: an ecological study. J Obstet Gynaecol Res. 2023;49:930–7. https://doi.org/10.1111/jog.15543 National Center for Health Statistics. Birth data. https://www.cdc.gov/nchs/nvss/births.htm. Accessed 18 Aug 2025 Additional Declarations No competing interests reported. Supplementary Files AdditionalFiles.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7777057","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":532164332,"identity":"7851d115-d8c0-42a5-82f9-911bcb86b4b2","order_by":0,"name":"Mikayo Toba","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYFACHjApB8QGIAYzERogWox5SNaS2APVQhjYs/ce/PBzz7b0/WKHNzD8qGFgNydoC8+5ZMmeZ7dze6TTChh7jjEwWzYQ0iKRYyDNcACkJceAgbeBgdngAGEtxr+BWtJ5gFoY/xKpxQxkSwJICzNxtpw5l2bZc+C2Yc/ttILDMsckCPuFvb338I0fB27Ls89O3vjwTY1NMsEQQwFAJ0kkExk7SMCOdC2jYBSMglEw3AEAbEQ6OizGC5IAAAAASUVORK5CYII=","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":true,"prefix":"","firstName":"Mikayo","middleName":"","lastName":"Toba","suffix":""},{"id":532164334,"identity":"8dfe2358-2915-4320-abaa-9cd9156f43b3","order_by":1,"name":"Rie Oi","email":"","orcid":"","institution":"Tokyo Metropolitan Ohtsuka Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rie","middleName":"","lastName":"Oi","suffix":""},{"id":532164335,"identity":"4d86ba9b-11dc-4793-8cfa-e9a5da66698d","order_by":2,"name":"Mutsuko Moriwaki","email":"","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Mutsuko","middleName":"","lastName":"Moriwaki","suffix":""},{"id":532164336,"identity":"22e23df0-e210-45c3-87da-0346cb18c667","order_by":3,"name":"Masayuki Kakehashi","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Kakehashi","suffix":""},{"id":532164337,"identity":"eac67ec4-32f5-487b-a855-b9707c54ba13","order_by":4,"name":"Ayako Fudono","email":"","orcid":"","institution":"Institute of Science Tokyo hospital","correspondingAuthor":false,"prefix":"","firstName":"Ayako","middleName":"","lastName":"Fudono","suffix":""},{"id":532164339,"identity":"b733de8f-5865-4602-ac5d-36453dc3bd4b","order_by":5,"name":"Kiyohide Fushimi","email":"","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Kiyohide","middleName":"","lastName":"Fushimi","suffix":""},{"id":532164341,"identity":"9188686b-8279-4aae-85e6-c2d82f45b14f","order_by":6,"name":"Naoyuki Miyasaka","email":"","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Naoyuki","middleName":"","lastName":"Miyasaka","suffix":""}],"badges":[],"createdAt":"2025-10-04 03:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7777057/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7777057/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94047924,"identity":"567b8b59-b93a-4db6-93a1-635a81767cdf","added_by":"auto","created_at":"2025-10-21 23:18:57","extension":"tif","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":268016,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/309b5bd261fbd8aa138d8dc6.tif"},{"id":94047925,"identity":"7dc2cb72-54d5-4c50-bd6b-34600f50b72c","added_by":"auto","created_at":"2025-10-21 23:18:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":46112,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/23b3fb24a28ec70b94c12dad.docx"},{"id":94047930,"identity":"2ccab615-9fd6-4f8e-ada8-9342388880e9","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":306784,"visible":true,"origin":"","legend":"","description":"","filename":"Fig2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/c25d0f965ce1eb8203e19315.tif"},{"id":94049387,"identity":"3ae41011-71f2-40de-9799-f367c729e78d","added_by":"auto","created_at":"2025-10-21 23:34:58","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":890000,"visible":true,"origin":"","legend":"","description":"","filename":"Fig3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/255a356c3f89de0a8d67e342.tif"},{"id":94047933,"identity":"bd9d592e-59ba-4eb7-9221-ce727346fd7d","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"json","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9090,"visible":true,"origin":"","legend":"","description":"","filename":"e0b42c23ffbe458f8f032a1e3b0da6ec.json","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/2168df14103d4fc7941f2223.json"},{"id":94048878,"identity":"8086f931-5fe3-4609-9008-dc455ed9424d","added_by":"auto","created_at":"2025-10-21 23:26:58","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19056,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFiles.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/d4b17a0773ce8e441d8c6507.xlsx"},{"id":94047936,"identity":"e4a78163-0de6-4944-8244-b77f79df4d88","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119242,"visible":true,"origin":"","legend":"","description":"","filename":"e0b42c23ffbe458f8f032a1e3b0da6ec1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/302ea6696ddd2409bcfcf437.xml"},{"id":94047939,"identity":"b06fbe20-82ec-422c-896d-dd35de24f71d","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"tif","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":268016,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/ad934608d19d1bb71891d702.tif"},{"id":94048880,"identity":"dd9ff330-1d7a-4959-b37d-7b5abaaf5664","added_by":"auto","created_at":"2025-10-21 23:26:58","extension":"tif","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":306784,"visible":true,"origin":"","legend":"","description":"","filename":"Fig2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/777f21147f2f9acde285d570.tif"},{"id":94047942,"identity":"bc14f682-e90e-4b4c-bc8e-8ae4b7551854","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"tif","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":890000,"visible":true,"origin":"","legend":"","description":"","filename":"Fig3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/b8f3128ce9993c968ca83d92.tif"},{"id":94047941,"identity":"3c0b2c04-8ab3-4783-965a-ca4d1460337c","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":87031,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/3d0aec34d7faf2b680daf905.png"},{"id":94048877,"identity":"af00463b-8241-4380-9e00-0a8dfe17bae8","added_by":"auto","created_at":"2025-10-21 23:26:57","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65806,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/981fad0e526a0936472be8bd.png"},{"id":94048879,"identity":"003b7224-71c5-43f8-a470-40e5e52a5491","added_by":"auto","created_at":"2025-10-21 23:26:58","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":235980,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/c5f2cb06b65e92a6b9d2be7a.png"},{"id":94047940,"identity":"6902235a-6d59-473f-839d-ef47a9cb728c","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":118046,"visible":true,"origin":"","legend":"","description":"","filename":"e0b42c23ffbe458f8f032a1e3b0da6ec1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/fc886e937fbb8d3006948543.xml"},{"id":94047935,"identity":"a86c1f5a-2213-4ead-8a7a-85ef698d7df2","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":129203,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/22cd1c8ba07d266015f04f6d.html"},{"id":94047923,"identity":"74a94cad-4f4e-474e-94fc-9dd553ac62a9","added_by":"auto","created_at":"2025-10-21 23:18:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":351247,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of study population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe annual trends by duration of ritodrine administration were based on 164,407 patients from 720 hospitals who were hospitalized and received intravenous ritodrine hydrochloride from April 2012 to March 2023, excluding patients with a pregnancy of 37 weeks or more, less than 22 weeks, unknown gestational age, and those admitted for maternal transfer after discharge. The analysis of factors associated with AT included 156,356 patients, excluding patients with a mixed AT and MT who received ritodrine for exactly 3 days.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/7944f8bae80a041339380fbc.png"},{"id":94047926,"identity":"90719eda-a456-4a25-8b12-588354157c7e","added_by":"auto","created_at":"2025-10-21 23:18:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":440520,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInfusion period of ritodrine hydrochloride.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea: Infusion period of ritodrine hydrochloride in all patients（n=164,407）.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe utilization rate of acute tocolysis (≤2 days) showed an increasing trend (Jonckheere-Terpstra test: p=0.036).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb: Infusion period of ritodrine hydrochloride by hospital（n=720）.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe utilization rate by hospital was shown in a box plot. The variation between facilities had increased over time.\u003c/p\u003e\n\u003cp\u003eThe utilization rate of acute tocolysis (≤2 days) showed an increasing trend (Jonckheere-Terpstra test: p=0.016).\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/92270ef94812f21af11520af.png"},{"id":94047932,"identity":"5da5eba5-cc74-4e71-8dda-4a89328fccd8","added_by":"auto","created_at":"2025-10-21 23:18:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":952644,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFactors associated with short protocol: A multivariate logistic regression analysis\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe dependent variable was presence or absence of acute tocolysis (AT) and independent variables included preterm labor management factors (magnesium sulfate hydrate or antenatal corticosteroids administration), healthcare provision factors (academic hospital or perinatal medical center), region (reference: Hokkaido-Tohoku), fiscal year, and maternal obstetric complications (preterm premature rupture of membranes, hypertensive disorders of pregnancy, gestational age, placenta previa, multiple pregnancy, and cervical insufficiency).\u003c/p\u003e\n\u003cp\u003e*1: magnesium sulfate, *2: antenatal steroid, *3: preterm premature rupture of membranes, *4: hypertensive disorder of pregnancy\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/b6e7fa253395d8131679a847.png"},{"id":100367728,"identity":"e84e6294-50f3-479a-a492-3abdfd0af62f","added_by":"auto","created_at":"2026-01-16 07:57:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2835409,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/34360b03-b182-475f-b5be-8cec0a694603.pdf"},{"id":94047928,"identity":"ee556552-1e1d-46af-889d-a125fd3caea8","added_by":"auto","created_at":"2025-10-21 23:18:57","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":19056,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFiles.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7777057/v1/6421675fdce10ab752483f57.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Trends and Determinants of Acute Tocolysis Utilization in Japan: A Nationwide Retrospective Cohort Study","fulltext":[{"header":"Plain English summary","content":"\u003cp\u003ePreterm birth, when a baby is born before 37 weeks of pregnancy, is a leading cause of newborn death worldwide. Given the risk of adverse events for both mother and baby, most international guidelines recommend limiting the use of tocolytic agents to a maximum of 48 hours (acute tocolysis: AT) to allow time for steroid administration for fetal lung maturation and for the mother to return to the perinatal center.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJapan has one of the lowest rates of premature birth, neonatal death, and infant death in the world. Tocolytic therapy in Japan is often continued for more than 48 hours (maintenance tocolysis:MT), which differs from many international guidelines.\u003c/p\u003e\n\u003cp\u003eWe studied over 156,000 pregnant women in Japan who were given ritodrine to stop preterm labor between 2012 and 2023. We found that the utilization of acute tocolysis gradually increased over time, rising from approximately 16% to 24%. Although the use of AT has increased in university hospitals and large perinatal centers, some facilities are not actively utilizing AT. Differences in regions, types of hospitals, and the maternal obstetrics complications influenced whether AT or MT was adopted. Our findings highlight that the choice between AT and MT in Japan is influenced by a complex interplay of factors, including regional factors where the hospital is located, hospital characteristics, and maternal obstetric conditions. This suggests that treatment decisions are being made thoughtfully, taking into account the specific needs of patients and the resources available at each facility. Further research and dialogue are needed to explore how these practices can be optimized to improve outcomes while respecting the unique context of perinatal care in Japan.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eIn 2020, an estimated 13.4\u0026nbsp;million preterm births were reported worldwide, with approximately 1 in 10 newborns being delivered preterm [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Preterm birth is the leading cause of neonatal and under-five mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and increases the risk of severe childhood illnesses [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Globally, the preterm birth rate has remained relatively stable [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In developed countries, however, the increase in high-risk pregnancies due to maternal aging and assisted reproductive technologies has led to more cases of spontaneous preterm births and medically indicated preterm births, in which early delivery or cesarean section is planned for medical reasons [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo address this issue, in 2023, the World Health Organization (WHO) recommended the appropriate use of tocolytic agents and the administration of antenatal corticosteroids [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Among these recommendations, tocolytic agents are recommended in cases of preterm labor to allow time for antenatal corticosteroid administration and ensure sufficient time for maternal transfer to tertiary medical centers equipped with neonatal intensive care units (NICUs) and facilities for preterm infant care. However, the use of tocolytic agents is recommended to be limited to acute tocolysis (AT) for up to 48 hours [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSince the 1980s, betamimetics have been widely used as tocolytic agents worldwide. However, in 2013, the European Medicines Agency concluded that high doses of short-acting betamimetics pose a significant risk of severe cardiovascular side effects for both mother and fetus. Consequently, the agency withdrew approval for oral and suppository formulations and restricted the use of injectable formulations to a maximum of 48 hours [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The World Health Organization (WHO) and the National Institute for Health and Care Excellence recommend the use of nifedipine as a tocolytic agent [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The American College of Obstetricians and Gynecologists does not specify a first-line tocolytic agent, but nifedipine and indomethacin are the most commonly used [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn 2020, the preterm birth rate in Japan was 5.48%, and the perinatal mortality and neonatal mortality rates were 3.2 and 0.8 per 1,000 live births, respectively, which are the lowest worldwide, indicating that perinatal healthcare in Japan is at the highest global standard [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These outcomes are believed to be largely attributed to Japan\u0026rsquo;s advanced perinatal healthcare system, including the development and functionality of advanced NICUs, the establishment of perinatal medical networks, the widespread availability and high quality of prenatal care, and advancements in techniques for managing complications [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, the treatment of preterm labor in Japan is unique globally. First, the tocolytic drugs approved in Japan are limited to beta-agonists such as ritodrine hydrochloride (ritodrine) and magnesium sulfate. Furthermore, both preterm labor cases and threatened preterm labor cases, such as those presenting with uterine contractions alone, are eligible for tocolytic therapy. These drugs are customarily administered for 48 hours or longer as maintenance tocolysis (MT) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The Japan Society of Obstetrics and Gynecology (JSOG) does not restrict the use of MT [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Following global trends, ritodrine injections decreased by 42.68% in 2022 compared to 2014 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Caution regarding ritodrine administration is thought to be driving this decline although the actual situation remains unclear [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The WHO emphasizes the need for consistency between guidelines and clinical protocols at the global, national, regional, and facility levels, as well as the need for clear standards in national guidelines regarding the appropriate use of tocolytic agents and acceptable regimens [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, no study in the literature to date has comprehensively evaluated current tocolytic therapy practices in Japan or explored factors influencing the choice of AT. In this study, we hypothesized that (a) the AT utilization rate has been increasing annually, reflecting a gradual shift toward international practice; (b) patient characteristics, including maternal obstetric complications, differ between those receiving AT and those receiving MT, and (c) hospital perinatal healthcare capabilities and regional differences influence the utilization pattern of tocolytic therapy. To test these hypotheses and provide evidence for evaluating the current status of tocolytic practices in Japan, we aimed to examine nationwide trends in AT utilization rates during the study period and explore factors associated with AT.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study, we utilized data from the Diagnosis Procedure Combination (DPC) database. The DPC is a patient categorization system for acute care inpatients in Japan, designed to enhance transparency and visibility in acute-stage medical care. These systems were introduced in 2003 by the Ministry of Health, Labor and Welfare as an inclusive payment model and have been utilized for acute hospital care and distribution of medical resources. This system includes acute care hospitals across Japan who submit data on medical procedures to the government [26]. As of 2023, the DPC database covered 1,761 facilities and 483,459 beds, accounting for 24.9% of general hospitals and 54.5% of beds in Japan. The DPC database collects data such as diagnoses associated with ICD-10 (International Classification of Diseases, 10th Revision) codes as well as patient demographics, including age, sex, existing comorbidities, complications arising after admission, admission and discharge dates, discharge outcomes, destinations after discharge, medications, in-hospital mortality, gestational age at admission, delivery during hospitalization, and details of surgical procedures [27]. Numerous studies on data reliability and clinical epidemiology have been conducted using this database [28\u0026ndash;30].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study participants were pregnant women aged 22⁺0 to 36⁺6 weeks of gestation age who were hospitalized between April 1, 2012, and March 31, 2023, and received ritodrine hydrochloride injection. Patients with unknown gestational age and those transferred from another hospital were excluded, as the treatment status at the previous hospital was unknown. The DPC database collects medication data daily. Among patients who received ritodrine for 3 days, some received it for less than 48 hours (AT) and others for more than 48 hours (MT); therefore, in this study, patients who received ritodrine injections for 2 days or less (within 48 hours) were classified as the AT group, and patients who received ritodrine injections for 4 days or more (more than 48 hours) were classified as the MT group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe variables analyzed in this study included maternal age; the Charlson Comorbidity Index [31, 32]; obstetric diseases\u0026mdash;such as preterm premature rupture of membranes (pPROM), hypertensive disorder of pregnancy (HDP), placenta previa, and cervical insufficiency; pregnancy status\u0026mdash;specifically gestational age and singleton pregnancy\u0026mdash;along with academic hospital status, perinatal medical center designation, hospital region, and fiscal year at admission. The hospitals were categorized into six regions based on geographical location: Hokkaido-Tohoku, Kanto, Chubu, Kansai, Chugoku-Shikoku, and Kyushu-Okinawa.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, we measured the AT utilization rate on both a patient-by-patient and a hospital-by-hospital basis. We analyzed annual trends in AT utilization rates using the Jonckheere-Terpstra test, to evaluate the presence of monotonic trends over time. Next, patients were divided into groups according to the method of tocolytic agent administration, after which patient and hospital characteristics were summarized using appropriate descriptive statistics. Continuous variables are expressed as means with standard deviations (SD) and were compared between groups using the Mann\u0026ndash;Whitney U test. Categorical variables are presented as frequencies with percentages and were compared using the chi-square test. Logistic regression analysis (forced entry method) was then performed with AT utilization as the dependent variable. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). SPSS version 30 (IBM, Chicago, Illinois, USA) was used for all analyses, and the significance level was set at 5% (two-tailed test).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institute of Science Tokyo Faculty of Medicine Ethics Review Committee approved this study (approval number: M2000-788; date of approval: December 19, 2023). The committee waived the requirement for informed consent because all personal information was excluded, and de-identified data were provided to the researchers for secondary use. This study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003eDuring the study period, 191,201 hospitalized patients received ritodrine infusion. The duration of ritodrine administration was assessed for 164,407 patients at 720 hospitals, after excluding patients with an unknown age at admission, patients with an age of 37 weeks or more, or patients with an age of less than 22 weeks, and patients transferred from multiple facilities (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe patient-level AT utilization rate increased from 15.08% to 22.26% over the past 11 years. In 2012, 30.68% of patients belonged to the \u0026ge;\u0026thinsp;28-day group, but this proportion decreased by 7.56% over the past 11 years. The 21\u0026ndash;27-day group also decreased by 1.55%, while the 7\u0026ndash;13-day and 14\u0026ndash;20-day groups remained stable, and the 4\u0026ndash;6-day and \u0026le;\u0026thinsp;2-day groups increased (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, Additional file 1). The AT utilization rate by hospitals also showed a monotonically increasing trend, although the variation between hospitals increased over time (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWe compared patient characteristics between the AT and MT groups among 156,356 patients at 720 facilities, excluding cases in which ritodrine was administered for 3 days (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe patient characteristics according to the duration of ritodrine administration are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of the patients was 31.92\u0026thinsp;\u0026plusmn;\u0026thinsp;5.48 years in the AT group and 31.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.41 years in the MT group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The mean gestational age at the time of hospitalization was 31.89\u0026thinsp;\u0026plusmn;\u0026thinsp;4.41 weeks, 29.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.40 weeks respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Pregnant women with multiple pregnancies, placenta previa, or cervical insufficiency were more likely to undergo MT, whereas those with pPROM or HDP were more likely to undergo AT. Pregnant women in academic hospitals and perinatal centers were more likely to receive AT. The incidence of antenatal corticosteroid administration was 23.90% for AT and 21.99% for MT (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the incidence of concomitant use of magnesium sulfate hydrate use was 19.05% for AT and 23.30% for MT (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of the participants according of ritodrine hydrochloride infusion (N\u0026thinsp;=\u0026thinsp;156,356)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAcute\u003c/p\u003e\u003cp\u003etocolysis\u003csup\u003e*2\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eN=29,314\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eMaintenance\u003c/p\u003e\u003cp\u003etocolysis *1\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;127,042\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ep\u003csup\u003e*3\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMaternal characteristics of admission\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years) [mean, SD\u003csup\u003e*\u003c/sup\u003e4]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational age (weeks) [mean, SD\u003csup\u003e*\u003c/sup\u003e4]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003csup\u003e*\u003c/sup\u003e5 (kg/m\u003csup\u003e2\u003c/sup\u003e) [mean, SD\u003csup\u003e*\u003c/sup\u003e4]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epPROM\u003csup\u003e*6\u003c/sup\u003e, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6,607\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10,691\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMultiple pregnancy, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,362\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15,010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlacenta previa, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,692\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10,285\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCervical insufficiency, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,172\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8,454\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational diabetes mellitus, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,352\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7,259\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertensive disorders of pregnancy, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,639\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4,982\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCCI\u003csup\u003e*\u003c/sup\u003e7, \u0026ge;\u0026thinsp;1, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e847\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3,769\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.481\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eInstitution\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcademic hospital, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8,442\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34,042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e26.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePerinatal medical center, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11,986\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e40.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e49,563\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e39.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRegions of the hospital\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHokkaido-Tohoku, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,790\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21,578\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e16.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKanto, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7,769\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e26.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32,546\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e25.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChubu, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5,477\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26,779\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKansai, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5,401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19,748\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e15.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChugoku-Shikoku, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,764\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16,297\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKyushu-Okinawa, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10,094\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.95\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFiscal year\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2012, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,774\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9,512\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"10\" rowspan=\"11\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2013, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,814\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9,825\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2014, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,429\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,567\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2015, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,336\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11,868\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2016, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11,290\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2017, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,057\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10,545\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2018, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,564\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11,047\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,339\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13,387\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,503\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,661\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,809\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13,104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,498\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11,236\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePreterm labor management\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACS\u003csup\u003e*\u003c/sup\u003e8, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7,005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27,934\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMagnesium sulfate hydrate, n,%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5,583\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29,600\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e23.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*1\u003c/sup\u003e maintenance tocolysis: ritodrine hydrochloride infusion for exceeding 4 days\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*2\u003c/sup\u003e acute tocolysis: ritodrine hydrochloride infusion for 2 days or less\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*3\u003c/sup\u003e continuous variable: Mann-Whitney U test, discrete variable: χ\u003csup\u003e2\u003c/sup\u003e test\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*4\u003c/sup\u003e standard deviation\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*5\u003c/sup\u003e body mass index\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*6\u003c/sup\u003e preterm premature rupture of membranes\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*7\u003c/sup\u003e Charlson comorbidity index\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*8\u003c/sup\u003e antenatal corticosteroids administration\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe results of logistic regression analysis of factors influencing the indication for AT are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Additional file 2. Admission to an academic hospital (aOR: 1.16, 95% CI: 1.12\u0026ndash;1.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), admission to a perinatal center (aOR: 1.12, CI: 1.08\u0026ndash;1.15, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and not receiving combination therapy with magnesium sulfate (aOR: 1.10, CI: 1.06\u0026ndash;1.15, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were associated with AT use. The association with AT also differed by region, with Kyushu-Okinawa (aOR: 1.79, CI: 1.70\u0026ndash;1.90, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) showing the strongest association with AT. In addition, compared with that in 2012, the association with AT became stronger over time from 2018 onward (aOR: 1.21, CI: 1.13\u0026ndash;1.129, aOR: 1.25, CI: 1.17\u0026ndash;1.33, aOR: 1.38, CI: 1.46\u0026ndash;1.56, aOR: 1.46, CI: 1.37\u0026ndash;1.56, aOR: 1.55, CI: 1.45\u0026ndash;1.66, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for each).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAmong maternal obstetrics complications, pPROM and HDP were strongly associated with AT (aOR: 3.18, CI: 3.06\u0026ndash;3.30, aOR: 1.52, CI: 1.43\u0026ndash;1.62, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for each), while twins and placenta previa were strongly associated with MT (aOR: 0.64, CI: 0.61\u0026ndash;0.67, aOR: 0.67, CI: 0.63\u0026ndash;0.71, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for each).The association with AT increased by 1.13 times for each additional week of gestational age.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis nationwide retrospective cohort study is the first to report an 11-year transitional trend in AT and obstetric factors influencing the choice of AT in 156,356 Japanese women who underwent ritodrine infusion for preterm labor.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTrends in Acute Tocolysis adoption\u003c/h2\u003e\u003cp\u003eThere is a lack of evidence that continuing tocolytic therapy beyond 48 hours improves neonatal outcomes; therefore, international guidelines and most countries recommend AT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Conversely, adherence to guidelines is reported to be low, and in actual clinical practice, MT after AT and the administration of tocolytic agents for threatened preterm labor are still performed [\u003cspan additionalcitationids=\"CR34 CR35 CR36\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Rousseau et al. identified barriers to guideline adherence, including physicians over 50 years of age, those working in non-university hospitals, and those fearing change [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Additionally, Lee et al. stated that patient opinion plays a major role in obstetricians' decision-making, and that maintenance medications may be prescribed based on the patient's request [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn Japan, ritodrine is the first-line drug for preterm labor, and its use for MT aligns with both domestic guidelines and the package insert [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The JSOG guidelines, revised every three years since 2008, have played a key role in maintaining Japan\u0026rsquo;s low preterm birth rate, even as maternal aging and the use of assisted reproductive technologies have increased [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the JSOG guidelines, the global recommendation for AT was first described in 2017. Ritodrine injection use in Japan decreased by 15.3% from 2017 to 2018, reaching 47.4% by 2022 compared to 2017 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] ༎Multivariate logistic regression analysis suggested that the association with AT has strengthened over time since 2018, likely due to the influence of guideline descriptions such as this. Furthermore, patients treated at academic hospitals and perinatal centers had a strong association with AT. Many of the committee members who create the guidelines are doctors employed at such facilities, and it is speculated that their frequent exposure to diverse information and publications from Japan and abroad influences their choice of AT. This finding is consistent with the results of Rousseau et al. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eRegional and Institutional Differences in Tocolysis Use\u003c/h2\u003e\u003cp\u003eThis study showed that regional factors are associated with AT use. Previous research has reported that differences in the provision of perinatal medical care between urban and rural areas, as well as availability of obstetricians and gynecologists, can influence medical decision-making and care for mothers and children [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. It is hypothesized that in areas with low population density and vast land area, factors such as long travel distances for obstetric checkups and births, difficulty in transporting the mother due to snow in winter, and availability of obstetricians and pediatricians can influence the choice of MT [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. These findings indicate the importance of selecting the most appropriate treatment for mothers and children based on local healthcare infrastructure and regional conditions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eMaternal and Obstetric Conditions Influencing Tocolysis\u003c/h2\u003e\u003cp\u003eThe utilization rate of AT has increased over the past 11 years; however, the preterm birth rate in Japan has remained stable at 5.48%\u0026ndash;5.75% for those under 37 weeks of gestation and 0.250%\u0026ndash;0.260% for those under 28 weeks of gestation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This rate is significantly lower than the preterm birth rate in the United States, which ranges from 9.7% to 10.4% [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Enengl et al. identified placenta previa as a specific indication for MT [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Similarly, our findings indicate that placenta previa is more strongly associated with MT. In contrast, conditions such as pPROM and severe hypertensive disorders of pregnancy (HDP), which require careful management due to the potential adverse effects of prolonged gestation on maternal and fetal outcomes, are more strongly associated with AT. Additionally, the early gestational age at admission tends to be more closely linked to MT. These findings suggest that the adoption of AT is not uniform across facilities and that treatment options are often selected based on the maternal condition and clinical context.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eImportance of Shared Decision-Making in Tocolysis\u003c/h2\u003e\u003cp\u003eRecommendations from the WHO, American College of Obstetricians and Gynecologists, and National Institute for Health and Care Excellence, among others, stipulate that when administering tocolytic therapy, adequate time and opportunity for shared decision-making should be provided among the pregnant woman, her family, and health care professionals regarding the short- and long-term effects of tocolytic therapy and preterm birth, decisions on resuscitation, limitations to survival, the benefits and harms of AT and MT, and long-term outcomes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Although we could not evaluate these processes in the present study, there remains a lack of evidence to guide appropriate decision-making based on policies, financial resources, geographical environments, and educational factors. Further studies are needed to address these gaps [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and Limitations of the Study\u003c/h2\u003e\u003cp\u003eThe strength of this study is that it investigated changes over an 11-year period across 720 hospitals, making it highly representative of Japan. In addition, the method of analyzing the actual status of treatment over a long period at multiple facilities using medical fee information, as well as examining factors related to changes in habitual treatment, can be applied to other countries. However, this study has some limitations inherent to perinatal retrospective cohort studies. First, there is the potential for confounding by indication, as patients receiving different durations of tocolysis may differ in terms of severity of preterm labor or other unmeasured clinical factors. Second, the use of an administrative database limits the availability of detailed clinical information, such as severity of the condition, specific treatment indications, and physician decision-making processes. Finally, as an observational study, it is fundamentally unable to establish causal relationships or definitively determine treatment effectiveness.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eImplications for Clinical Practice and Future Research\u003c/h2\u003e\u003cp\u003eThe findings of this study have important implications for clinical practice and education. By identifying factors that influence the use of AT, this study provides evidence for obstetricians to tailor treatment choices to guidelines and patient conditions. These results may also support shared decision-making. Furthermore, these findings may raise awareness among trainees about unresolved challenges in routinely performed tocolysis. Future prospective studies should compare maternal and neonatal outcomes of long-term versus short-term tocolysis in Japan and include economic evaluations of prolonged therapy. Therefore, to maintain and improve the quality of maternal and child health, further research is needed to establish protocols and evaluate available tocolytic drugs, taking into consideration work style reforms for doctors, shortages of obstetricians and pediatricians, and geographical issues.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAlthough the overall AT utilization rate has increased, differences exist in utilization status across facilities, and these gaps are widening. AT use tended to be influenced by factors such as hospital functions, obstetric complications, and regional characteristics. Further studies should explore the optimal tocolytic therapy strategy that minimizes maternal and fetal adverse events while improving neonatal outcomes. Simultaneously, it is important to communicate to pregnant woman, their families, and health care professionals that even with commonly used tocolytic therapies, there is ongoing debate regarding the choice of drug, dosage, and duration of administration.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eaOR, Adjusted Odds Ratio; AT, Acute Tocolysis; CI, Confidence Interval; DPC, Diagnosis Procedure Combination; GDM, Gestational Diabetes Mellitus; HDP, Hypertensive Disorders of Pregnancy; ICD-10, International Classification of Diseases, 10th Revision; JSOG, Japan Society of Obstetrics and Gynecology; MT, Maintenance Tocolysis; NICU, Neonatal Intensive Care Unit; pPROM, Preterm Premature Rupture of Membranes; SD, Standard Deviation; WHO, World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThe Institute of Science Tokyo Faculty of Medicine Ethics Review Committee approved this study (approval number: M2000-788; date of approval: December 19, 2023). The committee waived the requirement for informed consent because all personal information was excluded, and de-identified data were provided to the researchers for secondary use. This study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to contractual obligations with hospitals but are available from the co-author Kiyohide Fushimi on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe study was supported by the Sasakawa Health Foundation (2025-07). The funders had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eMT contributed to conceptualization, data curation, investigation, methodology, project administration, and visualization. MM was responsible for data curation, formal analysis, and visualization. RO and AF contributed to conceptualization and methodology. MK performed validation. KF contributed to methodology, provided resources, and\u0026nbsp;NM\u0026nbsp;supervised the study. All authors reviewed the results, contributed to manuscript writing, and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors would like to thank Shunji Shimoda of the National Hospital Organization Headquarters for providing technical support in the extraction and management of patient data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWHO. Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth. Accessed 6 Jun 2025\u003c/li\u003e\n\u003cli\u003eWardlaw T, You D, Hug L, Amouzou A, Newby H [UNICEF report]. UNICEF Report: enormous progress in child survival but greater focus on newborns urgently needed. Reprod Health. 2014;11:82. https://doi.org/10.1186/1742-4755-11-82\u003c/li\u003e\n\u003cli\u003eYadav S, Lee B, Kamity R. Neonatal respiratory distress syndrome. Treasure Island, FL: StatPearls Publishing; 2021\u003c/li\u003e\n\u003cli\u003ePatel RM. Short- and long-term outcomes for extremely preterm infants. Am J Perinatol. 2016;33:318\u0026ndash;28. https://doi.org/10.1055/s-0035-1571202\u003c/li\u003e\n\u003cli\u003evan Dommelen P, Verkerk PH, van Straaten HLM, Dutch Neonatal Intensive Care Unit Neonatal Hearing Screening Working Group. Hearing loss by week of gestation and birth weight in very preterm neonates. J Pediatr. 2015;166:840-3.e1.\u003c/li\u003e\n\u003cli\u003eOhuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402:1261\u0026ndash;71. https://doi.org/10.1016/S0140-6736(23)00878-4\u003c/li\u003e\n\u003cli\u003eHoffman MK. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, Number 234. Obstet Gynecol. 2021;138:945\u0026ndash;6. https://doi.org/10.1097/AOG.0000000000004612\u003c/li\u003e\n\u003cli\u003eTamura N, Hanaoka T, Ito K, Araki A, Miyashita C, Ito S, et al. Different risk factors for very low birth weight, term-small-for-gestational-age, or preterm birth in Japan. Int J Environ Res Public Health. 2018;15:369. https://doi.org/10.3390/ijerph15020369\u003c/li\u003e\n\u003cli\u003eWHO: recommendations on interventions to improve preterm birth outcomes. https://www.who.int/publications/i/item/9789241508988. Accessed 18 Aug 2025\u003c/li\u003e\n\u003cli\u003eWHO: recommendations on antenatal corticosteroids for improving preterm birth outcomes. https://www.who.int/publications/i/item/9789240057296\u003cu\u003e.\u003c/u\u003e Accessed 18 Aug 2025\u003c/li\u003e\n\u003cli\u003eNeilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2014;2014:CD004352. https://doi.org/10.1002/14651858.CD004352.pub3\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. https://www.ema.europa.eu/en/medicines/human/referrals/short-acting-beta-agonists. Accessed 18 Aug 2025\u003c/li\u003e\n\u003cli\u003eKashanian M, Shirvani S, Sheikhansari N, Javanmanesh F. A comparative study on the efficacy of nifedipine and indomethacin for prevention of preterm birth as monotherapy and combination therapy: a randomized clinical trial. J Matern Fetal Neonatal Med. 2020;33:3215\u0026ndash;20. https://doi.org/10.1080/14767058.2019.1570117\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence. Preterm labour and birth NICE guideline. https://www.nice.org.uk/guidance/ng25/resources/preterm-labour-and-birth-pdf-1837333576645. Accessed 18 Aug 2025\u003c/li\u003e\n\u003cli\u003eMayer C, Apodaca-Ramos I. Tocolysis. In: Treasure Island, FL: StatPearls Publishing; 2023. StatPearls [Internet]. p. 2025 Jan. PMID: 32965883.\u003c/li\u003e\n\u003cli\u003ee-Stat. Portal site of official statistics of Japan. https://www.e-stat.go.jp/dbview?sid=0003411613. Accessed 20 Sep 2025\u003c/li\u003e\n\u003cli\u003eShimano S, Yamada T, Cho K, Sengoku K, Mariya T, Saito T. Changes in preterm and extremely preterm birth rates in Japan after the introduction of obstetrical practice guidelines in 2008. J Obstet Gynaecol Res. 2023;49:2283\u0026ndash;94. https://doi.org/10.1111/jog.15722\u003c/li\u003e\n\u003cli\u003eSasaki Y, Ishikawa K, Yokoi A, Ikeda T, Sengoku K, Kusuda S, et al. Short- and long-term outcomes of extremely preterm infants in Japan according to outborn/inborn birth status. Pediatr Crit Care Med. 2019;20:963\u0026ndash;9. https://doi.org/10.1097/PCC.0000000000002037\u003c/li\u003e\n\u003cli\u003eNakamura Y. The role of maternal and child health (MCH) handbook in the era of sustainable development goals (SDGs). J Glob Health Sci. 2019;1:e24. https://doi.org/10.35500/jghs.2019.1.e24\u003c/li\u003e\n\u003cli\u003eJapan Medical Association. https://www.med.or.jp/english/activities/pdf/2011_04/234_240.pdf. Accessed 18 Aug 2025\u003c/li\u003e\n\u003cli\u003eOkuda A, Inayama Y, Mizuno K, Takeuchi M, Kawakami K, Mandai M, et al. Long-term vs short-term tocolysis with ritodrine hydrochloride: propensity score-matched analysis. Eur J Obstet Gynecol Reprod Biol. 2023;282:77\u0026ndash;82. https://doi.org/10.1016/j.ejogrb.2023.01.011\u003c/li\u003e\n\u003cli\u003eJapan Society of Obstetrics and Gynecology. Guidelines for obstetrical practice in Japan 2023. Japanese. https://www.jsog.or.jp/activity/pdf/gl_sanka_2023.pdf\u003cu\u003e.\u003c/u\u003e Accessed 18 Aug 2025\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000177182.html Accessed 23 Sep 2025\u003c/li\u003e\n\u003cli\u003eYoneda SJ. Method to evaluate intravenous maintenance tocolysis for preterm labor. J Obstet Gynaecol Res. 2020;46:2518\u0026ndash;25. https://doi.org/10.1111/jog.14484\u003c/li\u003e\n\u003cli\u003eYamaji N, Suzuki H, Saito K, Swa T, Namba F, Vogel JP, et al. Tocolytic therapy inhibiting preterm birth in high-risk populations: A systematic review and meta-analysis. Children (Basel). 2023;10:443. https://doi.org/10.3390/children10030443\u003c/li\u003e\n\u003cli\u003eMatsui H, Jo T, Fushimi K, Yasunaga H. Outcomes after early and delayed rehabilitation for exacerbation of chronic obstructive pulmonary disease: a nationwide retrospective cohort study in Japan. Respir Res. 2017;18:68. https://doi.org/10.1186/s12931-017-0552-7\u003c/li\u003e\n\u003cli\u003eHayashida K, Murakami G, Matsuda S, Fushimi K. History and profile of diagnosis procedure combination (DPC): development of a real data collection system for acute inpatient care in Japan. J Epidemiol. 2021;31:1\u0026ndash;11. https://doi.org/10.2188/jea.JE20200288\u003c/li\u003e\n\u003cli\u003eMoriwaki M, Takae A, Toba M, Sasaki M, Ogata Y, Obayashi S, et al. Factors associated with proximal femoral fractures in older adults during hospital stay: a cross-sectional study. BMJ Qual Saf. 2025;34:234\u0026ndash;43.. https://doi.org/10.1136/bmjqs-2023-015655\u003c/li\u003e\n\u003cli\u003eToba M, Terauchi M, Moriwaki M, Obayashi S, Miyasaka N, Fushimi K. Fractures within 2 years of an obstetric hospitalization: analysis of nationwide administrative data in Japan. J Bone Miner Metab. 2022;40:748\u0026ndash;54. https://doi.org/10.1007/s00774-022-01336-4\u003c/li\u003e\n\u003cli\u003eMoriwaki M, Toba M, Takizawa M, Shimizu H, Tanaka H, Takahashi C, et al. Oral management improves patient outcomes in hematopoietic stem cell transplantation. Int Dent J. 2025;75:100822. https://doi.org/10.1016/j.identj.2025.04.003\u003c/li\u003e\n\u003cli\u003eQuan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173:676\u0026ndash;82. https://doi.org/10.1093/aje/kwq433\u003c/li\u003e\n\u003cli\u003eCharlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373\u0026ndash;83. https://doi.org/10.1016/0021-9681(87)90171-8\u003c/li\u003e\n\u003cli\u003eEnengl S, Rath W, Kehl S, Oppelt P, Mayr A, Stroemer A, et al. Differences between current clinical practice and evidence-based guideline recommendations regarding tocolysis\u0026mdash;an Austria-wide survey. Geburtshilfe Frauenheilkd. 2025;85:47\u0026ndash;55. https://doi.org/10.1055/a-2446-1828\u003c/li\u003e\n\u003cli\u003eNazifovic E, Husslein H, Lakovschek I, Heinzl F, Wenzel-Schwarz E, Klaritsch P, et al. Differences between evidence-based recommendations and actual clinical practice regarding tocolysis: a prospective multicenter registry study. BMC Pregnancy Childbirth. 2018;18:446. https://doi.org/10.1186/s12884-018-2078-5\u003c/li\u003e\n\u003cli\u003eRousseau A, Azria E, Baumann S, Deneux-Tharaux C, Senat MV. Do obstetricians apply the national guidelines? A vignette-based study assessing practices for the prevention of preterm birth. BJOG. 2020;127:467\u0026ndash;76. https://doi.org/10.1111/1471-0528.16039\u003c/li\u003e\n\u003cli\u003eStelzl P, Kehl S, Oppelt P, Mayr A, Fleckenstein T, Maul H, et al. Maintenance tocolysis, tocolysis in preterm premature rupture of membranes and in cervical cerclage\u0026mdash;a Germany-wide survey on the current practice after dissemination of the German guideline. J Perinat Med. 2023;51:775\u0026ndash;81. https://doi.org/10.1515/jpm-2022-0572\u003c/li\u003e\n\u003cli\u003eLee HH, Yeh CC, Yang ST, Liu CH, Chen YJ, Wang PH. Tocolytic treatment for the prevention of preterm birth from a Taiwanese perspective: a survey of Taiwanese obstetric specialists. Int J Environ Res Public Health. 2022;19:4222. https://doi.org/10.3390/ijerph19074222\u003c/li\u003e\n\u003cli\u003eHattori S, Sakata N, Ishimaru M, Tamiya N. Consolidation of the perinatal care system and workload of obstetricians: an ecological study in Japan. Front Glob Womens Health. 2023;4:1030443. https://doi.org/10.3389/fgwh.2023.1030443\u003c/li\u003e\n\u003cli\u003eUeda A, Nakakita B, Chigusa Y, Mogami H, Kato G, Ueshima H, et al.Regional disparities in primary Cesarean delivery rates in Japan: the role of obstetrician availability. AJOG Glob Rep. 2024;4:100366. https://doi.org/10.1016/j.xagr.2024.100366\u003c/li\u003e\n\u003cli\u003eSaito Y, Asakura T, Takashi K, Umazume T, Watari H, Tamakoshi A. Relationship between out-of-facility deliveries and distance and travel time to delivery facilities in Hokkaido, Japan: an ecological study. J Obstet Gynaecol Res. 2023;49:930\u0026ndash;7. https://doi.org/10.1111/jog.15543\u003c/li\u003e\n\u003cli\u003eNational Center for Health Statistics. Birth data. https://www.cdc.gov/nchs/nvss/births.htm. Accessed 18 Aug 2025\u003cbr\u003e \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"preterm labor, ritodrine, acute tocolysis, maintenance tocolysis, maternal adverse events","lastPublishedDoi":"10.21203/rs.3.rs-7777057/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7777057/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePreterm birth remains a leading cause of neonatal mortality worldwide. While Japan has exceptionally low perinatal and neonatal mortality rates, clinical practice for preterm labor often involves maintenance tocolysis (MT) with ritodrine, which differs from international guidelines recommending acute tocolysis (AT) for up to 48 hours. To evaluate the current status of tocolytic practices in Japan, we investigated nationwide trends in the shift from MT to AT use and identify factors associated with the utilization of AT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective cohort study analyzed data from 156,356 pregnant women admitted to 720 institutions between April 2012 and March 2023 who received ritodrine infusion for preterm labor. Annual trends in AT utilization rates were examined, and logistic regression analysis was performed to identify factors associated with AT. Factors associated with AT use, including hospital characteristics, regional differences, and maternal obstetric complications, were explored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe rate of AT utilization increased from 15.73% to 23.74% over the 11-year period, but variation among hospitals widened. University hospitals (adjusted odds ratio [aOR] = 1.16, p \u0026lt; 0.001), perinatal centers (aOR = 1.12, p \u0026lt; 0.001), preterm premature rupture of membranes (aOR = 3.18, p \u0026lt; 0.001), and pregnancy-induced hypertension (aOR = 1.52, p \u0026lt; 0.001) were associated with AT, while concomitant use of magnesium sulfate hydrate (aOR = 0.91, p \u0026lt; 0.001), multiple fetuses (aOR = 0.64, p \u0026lt; 0.001), and placenta previa (aOR = 0.67, p \u0026lt; 0.001) were negatively associated with AT utilization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eWhile the rate of AT utilization has increased over time, differences in utilization exist between facilities, suggesting that choice of AT is influenced by multiple factors, including the perinatal medical system, maternal obstetric complications, and regional characteristics. Further discussion and research are needed to optimize treatment strategies to maximize maternal and fetal safety and improve outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eNot applicable.\u003c/p\u003e","manuscriptTitle":"Trends and Determinants of Acute Tocolysis Utilization in Japan: A Nationwide Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:18:53","doi":"10.21203/rs.3.rs-7777057/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c285548-c656-4ae5-a501-23348e8b7d7f","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-13T09:43:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:18:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7777057","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7777057","identity":"rs-7777057","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}