Safety of herbal medicine in the postpartum period of a Korean Medicine hospital and postpartum care centre: protocol of a registry study (SAFEHERE-PC)
The postpartum period, as defined by the guidelines, refers to the first 6–8 weeks after childbirth. During this time, the body gradually returns to a state similar to that before pregnancy, as it recovers from the changes introduced by pregnancy and childbirth. Postpartum symptoms are common, with 47%–94% of women experiencing health problems even beyond 8 weeks after childbirth. The most common of these problems include fatigue, headaches, swelling and musculoskeletal pain. Postpartum depression is also highly prevalent. These physical and mental discomforts during the postpartum period affect the woman’s health and quality of life, as well as the health of the child. This can lead to potential complications in the neonate’s health, like delays in language development, the development of behavioural issues, and other cognitive or physical developmental delays ; therefore, the provision of appropriate treatment during the postpartum period is crucial. In South Korea, Korean medicine (KM) is commonly used alongside conventional medicine for postpartum care. KM treatment includes herbal medicine (HM), acupuncture, moxibustion, cupping therapy, KM physical therapy and other therapies. KM actively addresses various postpartum symptoms, such as pain, systemic symptoms, urogenital discomfort and mental-neurological symptoms. A survey of postpartum mothers who received traditional KM treatment showed that 78.68% expressed their intention to undergo the treatment again in future pregnancies. The satisfaction rate with HM treatment was remarkably high at 86.88%. However, some concerns about the safety of HM have been identified, and the drug utilisation review service of South Korea has not provided information regarding adverse reactions related to HM. Safety evidence for postpartum HM consumption in South Korea is primarily based on experimental studies focusing on the influence of herbal treatments on postpartum lactation and reports on safety and adverse reactions are insufficient. In order to address the lack of systematic information on adverse events (AEs) related to postpartum HM in Korea, we have established the following research questions: (1) What is the incidence rate of AEs after taking postpartum herbal medicine? (2) Which types of herbal medicines are associated with specific AEs? (3) What is the causality between the observed AEs and the herbal medicines? These questions focus on incidence rates, types of herbal medicines and their associated AEs, and the causality between the herbal medicines and the AEs. This data-driven and practical safety assessment aims to enhance patient safety and increase the applicability of these findings in clinical settings. To this end, this study will establish a registry of patients receiving HM treatment during the postpartum period and collect clinical data on treatments and AEs to build evidence evaluating the safety of HM use as follows: (1) collecting clinical data and information on AEs related to HM treatment in postpartum patients using a standardised protocol and (2) evaluating the causality of any AEs that occur during HM treatment using the WHO Uppsala Monitoring Centre (WHO-UMC) causality assessment and the Naranjo Algorithm Score.   Registry design This is a prospective observational registry for HM use during the postpartum period in a KM hospital and postpartum care centre. We aim to enrol a total of 1000 eligible patients between March 2024 and June 2027. The study will focus on postpartum patients admitted to the postpartum care centre at Woosuk KM hospital (the KM Gynaecology and Obstetric Department) who receive HM treatment and voluntarily consent to the collection of their clinical data. Woosuk KM Hospital has been operating postpartum wards and postpartum care centre since 1999 and has also been involved in regional public postpartum healthcare project. As the only KM hospital with a postpartum care centre in South Korea, over 90% of postpartum mothers using the centre use KM gynaecology and obstetric department for postpartum treatment and take HM. In clinical settings, decoction forms of HM are the most popular oral dosage forms administered in South Korea. In this registry, HM will be administered as decoctions as prescribed in Korean clinical practice, allowing for the addition or subtraction of herbs based on the patient’s condition, without prescription restrictions. KM treatment includes acupuncture, moxibustion, cupping, Chuna manipulation and KM physical therapies and will adhere to the scope of routine medical care. Throughout the hospitalisation period at the postpartum care centre, demographic information, medical history, AEs and treatment details, including HM prescriptions and concomitant medication usage, will be collected for analysis. An online survey will be conducted 14 days (±3 days) postdischarge to assess potential adverse reactions for patients receiving additional HM prescriptions after discharge. Participating researchers will adhere to standard operating procedures for KM treatment of postpartum patients to ensure synchronisation and standardisation of the process prior to the initiation of the study. Eligibility criteria The inclusion criteria for this registry are as follows: (1) women aged over 19 years; (2) patients admitted to the postpartum care centre at Woosuk KM Hospital within 6 months of childbirth (based on the date of delivery) and receiving HM treatment for postpartum conditions at the obstetrics and gynaecology department and (3) patients who have received sufficient explanation before registration, voluntarily agree to participate in this study and sign a written informed consent form approved by the institutional review board. The exclusion criteria are as follows: (1) patients who do not agree to register and (2) participants judged inappropriate for participating in this study. Data collection (outcome measures) After admission to the postpartum care centre at Woosuk KM Hospital, participants’ data will be collected orally, and written consent will be obtained from each participant at the first visit. The occurrence of AEs will be monitored daily during hospitalisation. shows data collection and follow-up schedules. Demographics: Demographic information, including birthday and age, will be gathered at the admission date. Anthropometric data: Height, weight and extracellular water will be measured on admission and discharge. Maternal health and delivery details: We will collect information on the overall maternal health status, including date of delivery; mode of delivery; gestational weeks; number of pregnancies/term births/premature births/miscarriages/surviving children and factors related to high-risk pregnancy status, such as advanced maternal age (35 years and older), assisted in vitro fertilisation, gestational hypertension and gestational diabetes, at the admission date. Additionally, we will gather the demographic characteristics and feeding methods of neonates. HM treatment: For the observation and collection of authentic clinical data, no restrictions will be imposed on the type or frequency of HM treatment. Treatments will be prescribed by physicians in the postpartum care centre of the KM hospital tailored to the participants’ condition, defined according to traditional Chinese medicine syndrome differentiation and treatment principles. Prescribed HM data include the herbal drug name, dosage and treatment duration of the HM administration. AEs: The occurrence of adverse reactions will be checked daily during hospitalisation. If an AE occurs, we will collect details of the AE, including AE start date, symptom descriptions, outcome, seriousness, action taken after AE, AE reappearance after reintroduction of suspected HM and treatment methods for AE. This includes the collection of concurrent medication information. If the participants continue HM intake after discharge, we will check for adverse reactions associated with specific HM at 2 weeks after discharge. Data management and quality control We will use the myTrial Electronic Data Capture (NIKOM, Gyeongsan, Republic of Korea), an electronic case report form (eCRF) system validated by IT-KoM, for data collection. The designated investigator, who certifies the KM doctor, will enter and archive data in the eCRF system. Investigators access the data input form by inputting the web server address ( http://ecrf.nikom.or.kr ) from a remote computer with internet connectivity and log in using the provided user identity and password furnished by the website administrator. Periodic reviews of each case entered into the registry will be conducted, and data queries will be generated as per the data monitoring manual. The data collected for this study will be securely housed on a dedicated collection server with strict regulation of data access permissions. Sample size calculation Based on a study by Lessing et al , which suggested that the spread of AE decreases rapidly in sample sizes exceeding 1000, our study will aim to recruit a minimum of 1000 patients. The study is scheduled to commence in March 2024 and conclude in June 2027. The number of patients admitted to the postpartum care centre at Woosuk KM Hospital is approximately 300 per year, thus we expect to be able to achieve our target sample size. Statistical analysis and causality assessment For continuous data, such as demographic characteristics, we will present the mean and SD. Categorical data will be reported as frequencies and percentages. All statistical analyses will be conducted using two-sided tests, with a significance level of 5%. To assess the magnitude of adverse reactions, we will present the number of AEs as an OR with a 95% CI. In the case of AEs, we will evaluate their severity based on the criteria for severity assessment of AEs. Additionally, the causality of AEs will be assessed using the WHO-UMC causality assessment and the Naranjo Algorithm Score, similar to other studies that employed these tests in comparable situations. This assessment will be conducted by an independent Adverse Reaction Assessment Committee under the Regional Drug Safety Centre, Korea Institute of Drug Safety and Risk Management. In a future follow-up study, we intend to cross-reference this information with sociodemographic and obstetric data sourced from the Korean National Health Insurance Database. Patient and public involvement Patients were not involved in the development of the protocol and will not be involved in the implementation of the study.   This is a prospective observational registry for HM use during the postpartum period in a KM hospital and postpartum care centre. We aim to enrol a total of 1000 eligible patients between March 2024 and June 2027. The study will focus on postpartum patients admitted to the postpartum care centre at Woosuk KM hospital (the KM Gynaecology and Obstetric Department) who receive HM treatment and voluntarily consent to the collection of their clinical data. Woosuk KM Hospital has been operating postpartum wards and postpartum care centre since 1999 and has also been involved in regional public postpartum healthcare project. As the only KM hospital with a postpartum care centre in South Korea, over 90% of postpartum mothers using the centre use KM gynaecology and obstetric department for postpartum treatment and take HM. In clinical settings, decoction forms of HM are the most popular oral dosage forms administered in South Korea. In this registry, HM will be administered as decoctions as prescribed in Korean clinical practice, allowing for the addition or subtraction of herbs based on the patient’s condition, without prescription restrictions. KM treatment includes acupuncture, moxibustion, cupping, Chuna manipulation and KM physical therapies and will adhere to the scope of routine medical care. Throughout the hospitalisation period at the postpartum care centre, demographic information, medical history, AEs and treatment details, including HM prescriptions and concomitant medication usage, will be collected for analysis. An online survey will be conducted 14 days (±3 days) postdischarge to assess potential adverse reactions for patients receiving additional HM prescriptions after discharge. Participating researchers will adhere to standard operating procedures for KM treatment of postpartum patients to ensure synchronisation and standardisation of the process prior to the initiation of the study.   The inclusion criteria for this registry are as follows: (1) women aged over 19 years; (2) patients admitted to the postpartum care centre at Woosuk KM Hospital within 6 months of childbirth (based on the date of delivery) and receiving HM treatment for postpartum conditions at the obstetrics and gynaecology department and (3) patients who have received sufficient explanation before registration, voluntarily agree to participate in this study and sign a written informed consent form approved by the institutional review board. The exclusion criteria are as follows: (1) patients who do not agree to register and (2) participants judged inappropriate for participating in this study.   After admission to the postpartum care centre at Woosuk KM Hospital, participants’ data will be collected orally, and written consent will be obtained from each participant at the first visit. The occurrence of AEs will be monitored daily during hospitalisation. shows data collection and follow-up schedules. Demographics: Demographic information, including birthday and age, will be gathered at the admission date. Anthropometric data: Height, weight and extracellular water will be measured on admission and discharge. Maternal health and delivery details: We will collect information on the overall maternal health status, including date of delivery; mode of delivery; gestational weeks; number of pregnancies/term births/premature births/miscarriages/surviving children and factors related to high-risk pregnancy status, such as advanced maternal age (35 years and older), assisted in vitro fertilisation, gestational hypertension and gestational diabetes, at the admission date. Additionally, we will gather the demographic characteristics and feeding methods of neonates. HM treatment: For the observation and collection of authentic clinical data, no restrictions will be imposed on the type or frequency of HM treatment. Treatments will be prescribed by physicians in the postpartum care centre of the KM hospital tailored to the participants’ condition, defined according to traditional Chinese medicine syndrome differentiation and treatment principles. Prescribed HM data include the herbal drug name, dosage and treatment duration of the HM administration. AEs: The occurrence of adverse reactions will be checked daily during hospitalisation. If an AE occurs, we will collect details of the AE, including AE start date, symptom descriptions, outcome, seriousness, action taken after AE, AE reappearance after reintroduction of suspected HM and treatment methods for AE. This includes the collection of concurrent medication information. If the participants continue HM intake after discharge, we will check for adverse reactions associated with specific HM at 2 weeks after discharge.   We will use the myTrial Electronic Data Capture (NIKOM, Gyeongsan, Republic of Korea), an electronic case report form (eCRF) system validated by IT-KoM, for data collection. The designated investigator, who certifies the KM doctor, will enter and archive data in the eCRF system. Investigators access the data input form by inputting the web server address ( http://ecrf.nikom.or.kr ) from a remote computer with internet connectivity and log in using the provided user identity and password furnished by the website administrator. Periodic reviews of each case entered into the registry will be conducted, and data queries will be generated as per the data monitoring manual. The data collected for this study will be securely housed on a dedicated collection server with strict regulation of data access permissions.   Based on a study by Lessing et al , which suggested that the spread of AE decreases rapidly in sample sizes exceeding 1000, our study will aim to recruit a minimum of 1000 patients. The study is scheduled to commence in March 2024 and conclude in June 2027. The number of patients admitted to the postpartum care centre at Woosuk KM Hospital is approximately 300 per year, thus we expect to be able to achieve our target sample size.   For continuous data, such as demographic characteristics, we will present the mean and SD. Categorical data will be reported as frequencies and percentages. All statistical analyses will be conducted using two-sided tests, with a significance level of 5%. To assess the magnitude of adverse reactions, we will present the number of AEs as an OR with a 95% CI. In the case of AEs, we will evaluate their severity based on the criteria for severity assessment of AEs. Additionally, the causality of AEs will be assessed using the WHO-UMC causality assessment and the Naranjo Algorithm Score, similar to other studies that employed these tests in comparable situations. This assessment will be conducted by an independent Adverse Reaction Assessment Committee under the Regional Drug Safety Centre, Korea Institute of Drug Safety and Risk Management. In a future follow-up study, we intend to cross-reference this information with sociodemographic and obstetric data sourced from the Korean National Health Insurance Database.   Patients were not involved in the development of the protocol and will not be involved in the implementation of the study.   This registry was approved by the Institutional Review Board of the Woosuk KM Hospital of Woosuk University, Jeonju, Republic of Korea (WSOH IRB H2311-03-01). Written informed consent will be obtained from all participants before enrolment in the study. The results will be disseminated in peer-reviewed journals and conference presentations.   