Signal Mining and Analysis of Adverse Events in Children Using Growth Hormones: A Real-World Study Based on FAERS

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Methods: Data on children under 18 years of agefrom the FAERS database, covering the first quarter of 2004 to the first quarter of 2024, were extracted via the OpenVigil 2.1 tool. The reporting odds ratio (ROR) was employed to analyze adverse event signals related to growth hormones. Results: A total of 10,487 ADE reports for children using growth hormones were obtained, revealing 381 risk signals across 20 organ systems. The top five system organ categories on the basis of the number of reports were general disorders and administration site conditions (29.82%), investigations (20.11%), musculoskeletal and connective tissue disorders (13.51%), nervous system disorders (13.15%), and neoplasms benign, malignant and unspecified (6.47%). Among the positive signals not mentioned in the product labeling, the top five included non-high-density lipoprotein cholesterol increased, blood 25-hydroxycholecalciferol decreased, blood urea nitrogen/creatinine ratio increased, globulins decreased, elbow deformity. Conclusion: The signal intensity associated with muscle, skeletal, and neurological abnormalities, as well as tumor occurrence in children via growth hormones, is relatively high. Continuous monitoring and enhanced medication oversight are necessary. Growth hormone Children FAERS Adverse events Signal mining Figures Figure 1 Introduction With improvements in people's living standards, parents are increasingly paying attention to children's height. The causes of short stature in children are complex and include growth hormone deficiency (GHD), idiopathic short stature (ISS), skeletal development abnormalities, and certain genetic syndromes [1]. Among these diseases, GHD is an endocrine metabolic disease caused by insufficient secretion of growth hormone (GH) from the anterior pituitary [2]. In the 1950s, exogenous GH was first used to treat children with GHD. Subsequently, recombinant human growth hormone (rhGH) was introduced in the late 1980s, and its role in promoting growth and improving final height has been well recognized [3]. After years of research, Turner syndrome, ISS, Noonan syndrome, Prader-Willi syndrome, small for gestational age (SGA), and severe burns have been approved as indications for rhGH both domestically and internationally. With the continuous deepening of research, it has also been found to have beneficial effects on neuroprotection and chronic kidney disease [4-5]. While rhGH is widely used in the clinic, adverse drug reactions (ADRs) related to bone health, glucose and lipid metabolism, the nervous system, and even tumors can occur [6]. Currently, comprehensive and systematic safety evaluations of rhGH usage in children are limited. This study uses data mining from the FDA Adverse Event Reporting System (FAERS) database to analyze and summarize all pharmacovigilance information regarding growth hormone drugs in children, promoting clinical safety and rational medication use. Materials and methods 1.1 Data sources The data for this study were obtained from the FDA Adverse Event Reporting System (FAERS) database, covering data from the first quarter of 2004 to the first quarter of 2024. Each quarterly dataset includes seven subfiles containing basic case information (DEMO), drug information (DRUG), indications for use (INDI), adverse event information (REAC), clinical outcomes (OUTC), reporting sources (RPSR), and treatment duration (THER). 1.2 Data Extraction and Organization This study utilized the drug vigilance tool OpenVigil 2.1, which was developed and validated by the University of Kiel in Germany, to query and extract data from FAERS [ 7 ]. The generic names "human growth hormone" and "somatotropin" were used as search terms, with filtering criteria set for patients aged 0–18 years. The data were extracted and downloaded included patients' ages, sex, medication information, outcomes, indications, reporters, and reporting cities. Growth hormone was treated as the primary suspected drug for data filtering and cleaning, with duplicate reports and reports related to other indications excluded. Finally, adverse event signals were organized and categorized via preferred terms (PT) and system organ -class (SOC) from the 26.1 version of the Medical Dictionary for Regulatory Activities (MedDRA). 1.3 Adverse Event Signal Mining The signal mining method employed in this study was the reporting odds ratio (ROR) from the disproportionality analysis. A 2x2 contingency table was used for calculations, where 'a' represents the number of adverse event reports for the target drug, 'b' represents the number of reports for other adverse events related to the target drug, 'c' represents the number of adverse event reports for other drugs, and 'd' represents the number of reports for other adverse events related to those other drugs. The ROR value, 95% confidence interval (CI), proportional reporting ratio (PRR), and χ² test results were calculated via the corresponding formulas. The calculation formulas are as follows: ROR = (a/c)/(b/d) 95% CI for ROR = \(\:{e}^{lnROR\pm\:1.96\sqrt{1/\text{a}+1/\text{b}+1/\text{c}+1/\text{d}}}\) PRR = [a/(a + c)]/[b/(b + d)] χ² =(ad-bc) 2 (a + b + c + d)/[(a + b)(c + d) (a + c)(b + d)] The criteria for detecting vigilance signals are as follows: (1) ADE report count ≥ 3; reports with fewer than 3 cases are not clinically significant; and (2) the lower limit of the 95% CI for the ROR > 1 [ 8 ]. Results 2.1 Annual Reports of ADE in Children Using Growth Hormones This study selected adverse event (ADE) data related to the use of growth hormones in children under 18 years old from the first quarter of 2004 to the first quarter of 2024. The annual number of reports is shown in Fig. 1 , which indicates a general increasing trend in the number of reports over the years. 2.2 Basic Information on ADE in Children Using Growth Hormones After searching and filtering, a total of 15,126 ADE reports were obtained for children under 18 years of age, with growth hormone as the primary suspected drug. The clinical characteristics of the patients are statistically described in Table 1 . In terms of sex distribution, the proportion of females (61.61%) was greater than that of males (36.39%). In terms of age, the age group of 6–12 years had the highest number of reports (48.87%). The top five reporting countries were the United States, Japan, Colombia, Canada, and Argentina, with the United States having the highest number of reports (62.68%). In terms of clinical outcomes for patients, approximately 20.37% of reports of serious adverse events associated with growth hormone were noted, with hospitalization being the most common outcome. Table 1 Basic information of ADE of growth hormone used by children Characteristics Case number Case proportion(%) Gender Male 5504 36.39 Female 9319 61.61 Unknown 303 2.00 Age ≤ 5 2070 13.69 6 ~ 12 7392 48.87 13 ~ 18 5664 37.45 Product Name(Top 5) Genotropin 6936 45.85 Omnitrope 1941 12.83 Norditropin 1308 8.65 Nutropin aq 1203 7.95 Saizen 1047 6.92 Indication(Top 5) Growth hormone deficiency 3861 25.53 Unknown indication 1849 23.32 Short stature 1243 8.22 Hypopituitarism 1181 7.81 Turner's syndrome 427 2.82 Reported Countries (Top five) America 9481 62.68 Japan 586 3.87 Colombia 485 3.21 Canada 357 2.36 Argentina 332 2.19 Outcome Unknown 7991 52.83 Other outcome 3941 26.05 Hospitalization 2389 15.79 Death 376 2.49 Life-Threatening 230 1.52 Disability 86 0.57 2.3 Results of signal detection An analysis was conducted on the 15,126 ADE reports with growth hormone as the primary suspected drug, and the reporting odds ratio (ROR) method was used to calculate and screen for positive signals. Those signals that were unrelated to the drug, such as product issues, social environment factors, various injuries and poisonings, procedural complications, and various surgeries and medical procedures, were excluded. In the end, 10,487 cumulative ADE reports were obtained, resulting in 381 positive signals that spanned 20 different system organ classes (SOCs). The results revealed that the top five SOCs on the basis of report numbers were general disorders and administration site conditions (29.82%), investigations (20.11%), musculoskeletal and connective tissue disorders (13.51%), nervous system disorders (13.15%), and neoplasms benign, malignant and unspecified (6.47%), as shown in Table 2 . The effective signals for growth hormone were ranked according to the number of ADE reports. Among the most common ADEs were injection site pain (1,088 cases), headache (987 cases), and arthralgia (334 cases), as indicated in Table 3 . When sorted by the ROR, the most significant associations included non-high-density lipoprotein cholesterol increased, insulin-like growth factor increased, CNS germinoma, craniopharyngioma, blood 25-hydroxycholecalciferol decreased, as shown in Table 4 . Among the positive signals not mentioned in the product labeling, the top five were non-high-density lipoprotein cholesterol increased, blood 25-hydroxycholecalciferol decreased, blood urea nitrogen/creatinine ratio increased, globulins decreased, elbow deformity. Table 2 System organ class of ADE signal number of children using growth hormone SOC (System Organ Class) Signal Count Report Count Percentage (%) General disorders and administration site conditions 40 3127 29.82 Investigations 112 2109 20.11 Musculoskeletal and connective tissue disorders 48 1417 13.51 Nervous system disorders 13 1379 13.15 Neoplasms benign, malignant and unspecified 50 679 6.47 Metabolism and nutrition disorders 17 375 3.58 Infections and infestations 13 306 2.92 Respiratory, thoracic and mediastinal disorders 8 257 2.45 Endocrine disorders 16 187 1.78 Eye disorders 8 140 1.33 Renal and urinary disorders 8 98 0.93 Psychiatric disorders 4 95 0.91 Congenital, familial and genetic disorders 14 90 0.86 Reproductive system and breast disorders 10 67 0.64 Skin and subcutaneous tissue disorders 6 47 0.45 Ear and labyrinth disorders 3 34 0.32 Gastrointestinal disorders 5 32 0.31 Cardiac disorders 3 25 0.24 Immune system disorders 1 13 0.12 Blood and lymphatic system disorders 2 10 0.10 Table 3 Top 20 ADE Reports of Children Using Growth Hormone PT (Preferred Term) SOC (System Organ Class) Report Count ROR (95% CI) PRR (χ²) Injection site pain General disorders and administration site conditions 1088 8.89(8.30–9.53) 8.18(5541.07) Headache Nervous system disorders 987 3.40 (3.18–3.64) 3.20 (1396.24) Arthralgia Musculoskeletal and connective tissue disorders 334 3.51 (3.13–3.94) 3.44 (525.68) Injection site haemorrhage General disorders and administration site conditions 309 12.79(11.21–14.61) 12.49 (2355.28) Injection site bruising General disorders and administration site conditions 305 18.07(15.70–20.80) 17.64 (3094.27) Pain in extremity Musculoskeletal and connective tissue disorders 253 3.40 (2.98–3.87) 3.35 (377.38) Pain General disorders and administration site conditions 241 1.57 (1.38–1.79) 1.56 (46.26) Malaise General disorders and administration site conditions 196 1.45(1.25–1.67) 1.44 (25.23) Insulin-like growth factor increased Investigations 192 315.88(199.23-500.82) 310.86(5567.41) Scoliosis Musculoskeletal and connective tissue disorders 135 16.74(13.59–20.61) 16.56 (1296.53) Blood glucose increased Investigations 134 3.05 (2.55–3.64) 3.02 (164.74) Growth retardation* Musculoskeletal and connective tissue disorders 103 4.05 (3.30–4.98) 4.03 (206.24) Papilloedema Eye disorders 99 7.49 (6.02–9.33) 7.44 (443.83) Insulin-like growth factor decreased Investigations 98 290.85(155.91-542.57) 288.49(2804.33) Sleep apnoea syndrome* Respiratory, thoracic and mediastinal disorders 98 12.95(10.24–16.37) 12.85 (758.50) Syncope* Nervous system disorders 87 1.51 (1.22–1.88) 1.51 (13.91) Back pain Musculoskeletal and connective tissue disorders 84 1.61 (1.30–2.01) 1.61 (17.96) Brain neoplasm Neoplasms benign, malignant and unspecified 83 25.05(18.81–33.37) 24.89 (1062.59) Intracranial pressure increased Nervous system disorders 81 4.49 (3.56–5.67) 4.47 (188.81) Blood alkaline phosphatase increased Investigations 81 4.44 (3.52–5.60) 4.42 (185.56) Note: * indicates that the drug instructions did not mention it Table 4 The top 20 ADE positive signal intensities for children using growth hormone PT (Preferred Term) SOC (System Organ Class) Report Count ROR (95% CI) PRR (χ²) Non-high-density lipoprotein cholesterol increased* Investigations 15 486.33 (64.23-3682.13) 485.73 (422.82) Insulin-like growth factor increased Investigations 192 315.88 (199.23-500.82) 310.86 (5567.41) CNS germinoma Neoplasms benign, malignant and unspecified 7 226.80 (27.90-1843.62) 226.67 (168.59) Craniopharyngioma Neoplasms benign, malignant and unspecified 75 187.98 (104.30-338.82) 186.82 (2019.99) Blood 25-hydroxycholecalciferol decreased* Investigations 40 185.65 (83.15-414.51) 185.04 (1062.52) Blood urea nitrogen/creatinine ratio increased* Investigations 43 155.26 (75.67-318.56) 154.71 (1109.46) Globulins decreased* Investigations 13 105.35 (34.35-323.16) 105.24 (291.06) Elbow deformity* Musculoskeletal and connective tissue disorders 3 97.17 (10.11-934.24) 97.15 (48.74) Bone density increased Investigations 3 63.78 (39.76-102.33) 63.52 (1038.21) Acromegaly Endocrine disorders 51 54.01 (19.63-148.64) 53.97 (175.02) Pituitary cyst* Endocrine disorders 5 53.99 (12.90-225.95) 53.97 (78.08) Mean platelet volume decreased* Investigations 8 43.20 (14.99-225.95) 43.18 (123.24) Fibroma Neoplasms benign, malignant and unspecified 5 40.49 (10.87-150.82) 40.48 (68.43) Blood follicle stimulating hormone increased* Investigations 12 38.896 (16.80-90.04) 38.86 (183.85) Mean cell haemoglobin concentration decreased* Investigations 17 36.75 (18.35–73.60) 36.70 (259.77) Epiphysiolysis Musculoskeletal and connective tissue disorders 61 36.092 (25.06–51.99) 35.91 (964.97) Neoplasm recurrence Neoplasms benign, malignant and unspecified 76 34.391 (24.90–47.50) 34.18 (1174.75) Vitamin D decreased Investigations 55 33.13 (22.75–48.25) 32.99 (828.97) Cholesteatoma Neoplasms benign, malignant and unspecified 6 32.40 (10.45-100.47) 32.38 (75.78) Pituitary enlargement Endocrine disorders 4 32.39 (8.1-129.54) 32.38 (45.73) Note: * indicates that the drug instructions did not mention it Discussion Growth hormone (GH) medications are widely used in children to treat various causes of short stature, and there is even a notable incidence of overtreatment. While recombinant human growth hormone (rhGH) is clinically effective, its safety concerns and long-term effects on children have garnered significant attention. This study analyzed the characteristics of adverse events (AEs) associated with growth hormone medications in children via the FAERS database, employing the ROR and PRR methods. 3.1 Analysis of adverse events related to growth hormone medications From the first quarter of 2004 to the first quarter of 2024, the number of ADEs reported for growth hormone use in children under 18 years of age generally increased, with a marked rise starting in 2017 and peaking in 2018, followed by a slight decline. The primary reasons for this trend include the prolonged time since the drug's market entry, the increasing variety of medications, and the growing clinical application of growth hormone, leading to an increase in ADE reports. However, public awareness of adverse reactions to growth hormones has also increased, resulting in more cautious prescribing practices among clinicians, better patient monitoring, and education, ultimately stabilizing the number of ADE reports. Among the 15,126 ADE reports included in this study, most were from children aged 6–12 years, the primary population treated for short stature. The sex distribution revealed a significantly greater number of females than males. There have been no reports indicating whether there is a difference in sensitivity to growth hormone medications between sexes, which warrants further exploration. Approximately 20.37% of reported adverse events were classified as serious, indicating considerable medication risk. 3.2 Analysis of common ADE signals related to growth hormone-mediated effects The study identified 10,487 ADE reports and 381 signals, covering 20 SOCs. The top five SOCs on the basis of report numbers were systemic diseases and various reactions at the site of administration; various examinations; musculoskeletal and connective tissue diseases; neurological disorders; and benign, malignant, or unspecified tumors. The most commonly reported ADEs include various reactions at injection sites, headaches, and abnormal laboratory findings. Additionally, risks such as increased intracranial pressure, slipped capital femoral epiphysis, and scoliosis are noted, which is consistent with common adverse reactions listed in the prescribing information and current research [ 9 – 10 ]. The various injection site reactions are likely associated with the high frequency of daily injections. The use of long-acting growth hormone may reduce the injection frequency and alleviate the psychological burden on children. Some studies suggest that growth hormone promotes skeletal growth via insulin-like growth factor-1 (IGF-1) but can lead to adverse effects such as scoliosis and slipped capital femoral epiphysis due to rapid growth and increased bone metabolism, although the overall incidence is low [ 11 – 12 ]. Growth hormone antagonizes insulin, inhibiting glucose utilization and causing transient increases in blood glucose and related laboratory indices. However, studies have shown that growth hormone does not increase the incidence of diabetes in children, although it may lead to earlier onset in those predisposed to diabetes in adulthood [ 13 – 14 ]. Some reports indicate that growth hormone can cause mild sodium and water retention, leading to benign intracranial hypertension, characterized by headaches, vomiting, and vision loss, which typically resolves quickly after discontinuation. This reaction may occur because growth hormone rapidly corrects cerebrospinal fluid shifts caused by long-term GH deficiency [ 6 , 15 ]. Tumor-related adverse reactions are a primary concern for parents, and this study revealed that malignant and unspecified tumor reactions accounted for 6.47% of the reports. Growth hormone is known to promote anabolic metabolism and cell mitosis, with IGF-1 exhibiting antiapoptotic properties, theoretically increasing the risk of tumorigenesis [ 16 ]. However, the National Cooperative Growth Study (NCGS) and the Pfizer International Growth Database (KIGS), along with the findings of most studies, suggest that growth hormone does not increase the risk of malignant tumors [ 12 , 17 – 21 ]. A recent article in The Lancet indicated that rhGH treatment does not affect overall cancer risk, although these studies have limitations [ 22 ]. The relatively high reporting rate of tumor-related adverse effects may be because individuals tend to be more sensitive to tumor-related health concerns than to other AEs, and patients in tumor-susceptible populations may already have existing tumors, potentially leading to secondary malignancies. The causal relationship between growth hormone and adverse tumor effects requires further research. 3.3 Analysis of Newly Suspected ADE Signals Related to Growth Hormone Medications Among the top 20 reporting numbers and positive signal strengths based on preferred terms (PTs), 12 new suspected positive signals were identified that were not documented in the product labeling. These included growth retardation, obstructive sleep apnea syndrome, elbow deformities, pituitary cysts, and several abnormal laboratory findings. Research indicates that short-term risks for sleep apnea syndrome often occur in children with baseline obstructive symptoms or after upper respiratory infections. In contrast, growth hormone treatment does not appear to impact sleep-disordered breathing [ 23 ]. Growth hormone has the ability to break down fat, leading to various effects on lipid profiles; rhGH therapy tends to increase high-density lipoprotein (HDL) and decrease low-density lipoprotein (LDL) [ 15 ]. Growth retardation could reflect individual differences in response to growth hormone therapy, with some children showing no significant effects or other underlying conditions causing stunted growth. Pituitary cysts and abnormal laboratory results may be related to the influence of growth hormone on endocrine function and metabolic growth, necessitating ongoing surveillance for new ADEs associated with growth hormone medications, particularly those that are novel and subtle. 3.4 Study Limitations ① This study relied on the FAERS database to conduct signal detection for ADEs related to growth hormone medications in children. As a voluntary reporting system, it may contain duplicate reports, incomplete data, weak causal relationships, or even erroneous information. ②The reporting countries were predominantly the United States, Japan, and Colombia, with lower representation from other countries, introducing a potential racial bias and underscoring the need for more safety monitoring data across diverse populations. ③While the study indicated a higher reported incidence of benign, malignant, and unspecified tumors, this finding contradicts some existing research, suggesting the need for in-depth and long-term follow-up studies to determine any causal relationship between growth hormone and tumors. Growth hormone has been widely used in children, and for nearly 40 years, the safety data surrounding its use have been generally good. However, many issues persist, particularly regarding its long-term effects on children, thus highlighting the importance of rigorous monitoring and follow-up. Declarations Acknowledgements Not applicable. Author Contributions Design of the study: YF; Data acquisition and analysis: WX; Draft the manuscript: YF, WX; Manuscript revise and final version approval: YF, WX, JA B contributed equally to this work. All authors have read and approved the final manuscript. Funding This work was supported by the Suzhou Medical Engineering Collaborative Innovation Research Project (SZM2022015). Funders had no influence on the design of the study, the data collection and analysis, and the manuscript writing. Ethics approval and consent to participate Anonymized data were collected from a publicly available database (FAERS database, https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS. html), the need for ethics approval and consent was waived. Consent for publication Not applicable. Competing interests The authors declare no competing financial or non-financial interests that are directly or indirectly related to the work submitted for publication. 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Childhood growth hormone treatment: challenges, opportunities, and considerations. Lancet Child Adolesc Health. 2024;8(8):600-610. Miller JL, Shuster J, Theriaque D, et al. Sleep disordered breathing in infants with Prader-Willi syndrome during the first 6 weeks of growth hormone therapy: a pilot study. J Clin Sleep Med. 2009;5(5):448-453. Additional Declarations No competing interests reported. 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. 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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-4895744","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":340984913,"identity":"e7a53c13-bc8e-4607-a333-1d7362ebc421","order_by":0,"name":"Wan Xu","email":"","orcid":"","institution":"The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Wan","middleName":"","lastName":"Xu","suffix":""},{"id":340984918,"identity":"df0df7ea-f8af-43e1-ba21-a7f0b85bae0f","order_by":1,"name":"Jian-an Bao","email":"","orcid":"","institution":"The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Jian-an","middleName":"","lastName":"Bao","suffix":""},{"id":340984921,"identity":"e27a6ebc-9f7e-41cb-bf3f-89d5aee54f3d","order_by":2,"name":"Yao Fei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYBACxvbm4z8SKmzk2NgbiNTC3HMsQeLDmTRjPp4DRGphn+GjIDmz7XDiPIkEIrXwzuBhMOYFammTfLzxBkONTTRBLZKzew8k85xLN26TTiu2YDiWlttASIvhnHMJh3nKrGXbpHPMJBgbDhPWYn8jx7CZh42ZsU3yDJFaGGfkGDPOaHNWbJPgIVZLz7E0BlAgs/EA/ZJAjF+AUXmMARSV8u2HN974UGNDWAsyMCA6apC0kKpjFIyCUTAKRgYAAK9RQMIzkqeMAAAAAElFTkSuQmCC","orcid":"","institution":"The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University","correspondingAuthor":true,"prefix":"","firstName":"Yao","middleName":"","lastName":"Fei","suffix":""}],"badges":[],"createdAt":"2024-08-11 15:06:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4895744/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4895744/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66370180,"identity":"34d92e71-016d-420c-9adc-508f0c5f2609","added_by":"auto","created_at":"2024-10-11 04:27:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30636,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of ADE reports for children using growth hormones from Q1 2004 to Q1 2024.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4895744/v1/7a93123bfebc9f0c56292c35.png"},{"id":77694219,"identity":"be097dfb-0274-4194-85a3-bfcc2c562663","added_by":"auto","created_at":"2025-03-04 10:09:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020726,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4895744/v1/654a5498-46c0-46ac-927f-cb758f73985c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Signal Mining and Analysis of Adverse Events in Children Using Growth Hormones: A Real-World Study Based on FAERS","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith\u0026nbsp;improvements in\u0026nbsp;people's living standards, parents are increasingly paying attention to children's height. The causes of short stature in children are complex\u0026nbsp;and include\u0026nbsp;growth hormone deficiency (GHD), idiopathic short stature (ISS), skeletal development abnormalities, and certain genetic syndromes [1]. Among these\u0026nbsp;diseases, GHD is an endocrine metabolic disease caused by insufficient secretion of growth hormone (GH) from the anterior pituitary [2]. In the 1950s, exogenous GH was first used to treat children with GHD. Subsequently, recombinant human growth hormone (rhGH) was introduced in the late 1980s, and its role in promoting growth and improving final height has been well recognized [3]. After years of research, Turner syndrome, ISS, Noonan syndrome,\u0026nbsp;Prader-Willi\u0026nbsp;syndrome, small for gestational age (SGA), and severe burns have been approved as indications for rhGH both domestically and internationally. With the continuous deepening of research, it has also been found to have beneficial effects\u0026nbsp;on\u0026nbsp;neuroprotection and chronic kidney disease [4-5]. While rhGH is widely used in\u0026nbsp;the clinic, adverse drug reactions (ADRs) related to bone health, glucose and lipid metabolism, the nervous system, and even tumors can occur [6]. Currently, comprehensive and systematic safety evaluations of rhGH usage in children are limited. This study\u0026nbsp;uses\u0026nbsp;data mining from the FDA Adverse Event Reporting System (FAERS) database to analyze and summarize all pharmacovigilance information regarding growth hormone drugs in children, promoting clinical safety and rational medication use.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\n \u003ch2\u003e1.1 Data sources\u003c/h2\u003e\n \u003cp\u003eThe data for this study were obtained from the FDA Adverse Event Reporting System (FAERS) database, covering data from the first quarter of 2004 to the first quarter of 2024. Each quarterly dataset includes seven subfiles containing basic case information (DEMO), drug information (DRUG), indications for use (INDI), adverse event information (REAC), clinical outcomes (OUTC), reporting sources (RPSR), and treatment duration (THER).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e1.2 Data Extraction and Organization\u003c/h2\u003e\n \u003cp\u003eThis study utilized the drug vigilance tool OpenVigil 2.1, which was developed and validated by the University of Kiel in Germany, to query and extract data from FAERS [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. The generic names \u0026quot;human growth hormone\u0026quot; and \u0026quot;somatotropin\u0026quot; were used as search terms, with filtering criteria set for patients aged 0\u0026ndash;18 years. The data were extracted and downloaded included patients\u0026apos; ages, sex, medication information, outcomes, indications, reporters, and reporting cities. Growth hormone was treated as the primary suspected drug for data filtering and cleaning, with duplicate reports and reports related to other indications excluded. Finally, adverse event signals were organized and categorized via preferred terms (PT) and system organ -class (SOC) from the 26.1 version of the Medical Dictionary for Regulatory Activities (MedDRA).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e1.3 Adverse Event Signal Mining\u003c/h2\u003e\n \u003cp\u003eThe signal mining method employed in this study was the reporting odds ratio (ROR) from the disproportionality analysis. A 2x2 contingency table was used for calculations, where \u0026apos;a\u0026apos; represents the number of adverse event reports for the target drug, \u0026apos;b\u0026apos; represents the number of reports for other adverse events related to the target drug, \u0026apos;c\u0026apos; represents the number of adverse event reports for other drugs, and \u0026apos;d\u0026apos; represents the number of reports for other adverse events related to those other drugs. The ROR value, 95% confidence interval (CI), proportional reporting ratio (PRR), and \u0026chi;\u0026sup2; test results were calculated via the corresponding formulas. The calculation formulas are as follows:\u003c/p\u003e\n \u003cp\u003eROR = (a/c)/(b/d)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Heading\"\u003e95% CI for ROR =\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{e}^{lnROR\\pm\\:1.96\\sqrt{1/\\text{a}+1/\\text{b}+1/\\text{c}+1/\\text{d}}}\\)\u003c/span\u003e\u003c/span\u003e\u003c/div\u003e\n\u003cp\u003ePRR = [a/(a\u0026thinsp;+\u0026thinsp;c)]/[b/(b\u0026thinsp;+\u0026thinsp;d)]\u003c/p\u003e\n\u003cp\u003e\u0026chi;\u0026sup2; =(ad-bc)\u003csup\u003e2\u003c/sup\u003e(a\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d)/[(a\u0026thinsp;+\u0026thinsp;b)(c\u0026thinsp;+\u0026thinsp;d) (a\u0026thinsp;+\u0026thinsp;c)(b\u0026thinsp;+\u0026thinsp;d)]\u003c/p\u003e\n\u003cp\u003eThe criteria for detecting vigilance signals are as follows: (1) ADE report count\u0026thinsp;\u0026ge;\u0026thinsp;3; reports with fewer than 3 cases are not clinically significant; and (2) the lower limit of the 95% CI for the ROR\u0026thinsp;\u0026gt;\u0026thinsp;1 [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Annual Reports of ADE in Children Using Growth Hormones\u003c/h2\u003e \u003cp\u003eThis study selected adverse event (ADE) data related to the use of growth hormones in children under 18 years old from the first quarter of 2004 to the first quarter of 2024. The annual number of reports is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, which indicates a general increasing trend in the number of reports over the years.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Basic Information on ADE in Children Using Growth Hormones\u003c/h2\u003e \u003cp\u003eAfter searching and filtering, a total of 15,126 ADE reports were obtained for children under 18 years of age, with growth hormone as the primary suspected drug. The clinical characteristics of the patients are statistically described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In terms of sex distribution, the proportion of females (61.61%) was greater than that of males (36.39%). In terms of age, the age group of 6\u0026ndash;12 years had the highest number of reports (48.87%). The top five reporting countries were the United States, Japan, Colombia, Canada, and Argentina, with the United States having the highest number of reports (62.68%). In terms of clinical outcomes for patients, approximately 20.37% of reports of serious adverse events associated with growth hormone were noted, with hospitalization being the most common outcome.\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\u003eBasic information of ADE of growth hormone used by children\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase proportion(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e303\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u0026thinsp;~\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u0026thinsp;~\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5664\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProduct Name(Top 5)\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotropin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOmnitrope\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorditropin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1308\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNutropin aq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaizen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndication(Top 5)\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth hormone deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown indication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1849\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypopituitarism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTurner's syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReported Countries (Top five)\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmerica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9481\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e586\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColombia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e357\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArgentina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e332\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2389\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e376\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-Threatening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Results of signal detection\u003c/h2\u003e \u003cp\u003eAn analysis was conducted on the 15,126 ADE reports with growth hormone as the primary suspected drug, and the reporting odds ratio (ROR) method was used to calculate and screen for positive signals. Those signals that were unrelated to the drug, such as product issues, social environment factors, various injuries and poisonings, procedural complications, and various surgeries and medical procedures, were excluded. In the end, 10,487 cumulative ADE reports were obtained, resulting in 381 positive signals that spanned 20 different system organ classes (SOCs). The results revealed that the top five SOCs on the basis of report numbers were general disorders and administration site conditions (29.82%), investigations (20.11%), musculoskeletal and connective tissue disorders (13.51%), nervous system disorders (13.15%), and neoplasms benign, malignant and unspecified (6.47%), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe effective signals for growth hormone were ranked according to the number of ADE reports. Among the most common ADEs were injection site pain (1,088 cases), headache (987 cases), and arthralgia (334 cases), as indicated in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. When sorted by the ROR, the most significant associations included non-high-density lipoprotein cholesterol increased, insulin-like growth factor increased, CNS germinoma, craniopharyngioma, blood 25-hydroxycholecalciferol decreased, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Among the positive signals not mentioned in the product labeling, the top five were non-high-density lipoprotein cholesterol increased, blood 25-hydroxycholecalciferol decreased, blood urea nitrogen/creatinine ratio increased, globulins decreased, elbow deformity.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSystem organ class of ADE signal number of children using growth hormone\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOC (System Organ Class)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignal Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReport Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePercentage (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1417\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e679\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfections and infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e306\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e257\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEye disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal and urinary disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsychiatric disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital, familial and genetic disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReproductive system and breast disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEar and labyrinth disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTop 20 ADE Reports of Children Using Growth Hormone\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT (Preferred Term)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSOC (System Organ Class)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReport Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR (χ\u0026sup2;)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjection site pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.89(8.30\u0026ndash;9.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.18(5541.07)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e987\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.40 (3.18\u0026ndash;3.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.20 (1396.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArthralgia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e334\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.51 (3.13\u0026ndash;3.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.44 (525.68)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjection site haemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e309\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.79(11.21\u0026ndash;14.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.49 (2355.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjection site bruising\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.07(15.70\u0026ndash;20.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17.64 (3094.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain in extremity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.40 (2.98\u0026ndash;3.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.35 (377.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e241\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.57 (1.38\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.56 (46.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalaise\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.45(1.25\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.44 (25.23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin-like growth factor increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e315.88(199.23-500.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e310.86(5567.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScoliosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.74(13.59\u0026ndash;20.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.56 (1296.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood glucose increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.05 (2.55\u0026ndash;3.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.02 (164.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth retardation*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.05 (3.30\u0026ndash;4.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.03 (206.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapilloedema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEye disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.49 (6.02\u0026ndash;9.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.44 (443.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin-like growth factor decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e290.85(155.91-542.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e288.49(2804.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep apnoea syndrome*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.95(10.24\u0026ndash;16.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.85 (758.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSyncope*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.51 (1.22\u0026ndash;1.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.51 (13.91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBack pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.61 (1.30\u0026ndash;2.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.61 (17.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain neoplasm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.05(18.81\u0026ndash;33.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e24.89 (1062.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntracranial pressure increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNervous system disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.49 (3.56\u0026ndash;5.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.47 (188.81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood alkaline phosphatase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.44 (3.52\u0026ndash;5.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.42 (185.56)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: * indicates that the drug instructions did not mention it\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe top 20 ADE positive signal intensities for children using growth hormone\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT (Preferred Term)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSOC (System Organ Class)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReport Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR (χ\u0026sup2;)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-high-density lipoprotein cholesterol increased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e486.33 (64.23-3682.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e485.73 (422.82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin-like growth factor increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e315.88 (199.23-500.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e310.86 (5567.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCNS germinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e226.80 (27.90-1843.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e226.67 (168.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCraniopharyngioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e187.98 (104.30-338.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e186.82 (2019.99)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood 25-hydroxycholecalciferol decreased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e185.65 (83.15-414.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e185.04 (1062.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood urea nitrogen/creatinine ratio increased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e155.26 (75.67-318.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e154.71 (1109.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlobulins decreased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e105.35 (34.35-323.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e105.24 (291.06)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElbow deformity*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.17 (10.11-934.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e97.15 (48.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone density increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63.78 (39.76-102.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63.52 (1038.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcromegaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndocrine disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.01 (19.63-148.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e53.97 (175.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePituitary cyst*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndocrine disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53.99 (12.90-225.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e53.97 (78.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean platelet volume decreased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.20 (14.99-225.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e43.18 (123.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibroma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40.49 (10.87-150.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40.48 (68.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood follicle stimulating hormone increased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.896 (16.80-90.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38.86 (183.85)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean cell haemoglobin concentration decreased*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.75 (18.35\u0026ndash;73.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e36.70 (259.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpiphysiolysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.092 (25.06\u0026ndash;51.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35.91 (964.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoplasm recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.391 (24.90\u0026ndash;47.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e34.18 (1174.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.13 (22.75\u0026ndash;48.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32.99 (828.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCholesteatoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeoplasms benign, malignant and unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.40 (10.45-100.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32.38 (75.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePituitary enlargement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndocrine disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.39 (8.1-129.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32.38 (45.73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: * indicates that the drug instructions did not mention it\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eGrowth hormone (GH) medications are widely used in children to treat various causes of short stature, and there is even a notable incidence of overtreatment. While recombinant human growth hormone (rhGH) is clinically effective, its safety concerns and long-term effects on children have garnered significant attention. This study analyzed the characteristics of adverse events (AEs) associated with growth hormone medications in children via the FAERS database, employing the ROR and PRR methods.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Analysis of adverse events related to growth hormone medications\u003c/h2\u003e \u003cp\u003eFrom the first quarter of 2004 to the first quarter of 2024, the number of ADEs reported for growth hormone use in children under 18 years of age generally increased, with a marked rise starting in 2017 and peaking in 2018, followed by a slight decline. The primary reasons for this trend include the prolonged time since the drug's market entry, the increasing variety of medications, and the growing clinical application of growth hormone, leading to an increase in ADE reports. However, public awareness of adverse reactions to growth hormones has also increased, resulting in more cautious prescribing practices among clinicians, better patient monitoring, and education, ultimately stabilizing the number of ADE reports. Among the 15,126 ADE reports included in this study, most were from children aged 6\u0026ndash;12 years, the primary population treated for short stature. The sex distribution revealed a significantly greater number of females than males. There have been no reports indicating whether there is a difference in sensitivity to growth hormone medications between sexes, which warrants further exploration. Approximately 20.37% of reported adverse events were classified as serious, indicating considerable medication risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Analysis of common ADE signals related to growth hormone-mediated effects\u003c/h2\u003e \u003cp\u003eThe study identified 10,487 ADE reports and 381 signals, covering 20 SOCs. The top five SOCs on the basis of report numbers were systemic diseases and various reactions at the site of administration; various examinations; musculoskeletal and connective tissue diseases; neurological disorders; and benign, malignant, or unspecified tumors. The most commonly reported ADEs include various reactions at injection sites, headaches, and abnormal laboratory findings. Additionally, risks such as increased intracranial pressure, slipped capital femoral epiphysis, and scoliosis are noted, which is consistent with common adverse reactions listed in the prescribing information and current research [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe various injection site reactions are likely associated with the high frequency of daily injections. The use of long-acting growth hormone may reduce the injection frequency and alleviate the psychological burden on children. Some studies suggest that growth hormone promotes skeletal growth via insulin-like growth factor-1 (IGF-1) but can lead to adverse effects such as scoliosis and slipped capital femoral epiphysis due to rapid growth and increased bone metabolism, although the overall incidence is low [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Growth hormone antagonizes insulin, inhibiting glucose utilization and causing transient increases in blood glucose and related laboratory indices. However, studies have shown that growth hormone does not increase the incidence of diabetes in children, although it may lead to earlier onset in those predisposed to diabetes in adulthood [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Some reports indicate that growth hormone can cause mild sodium and water retention, leading to benign intracranial hypertension, characterized by headaches, vomiting, and vision loss, which typically resolves quickly after discontinuation. This reaction may occur because growth hormone rapidly corrects cerebrospinal fluid shifts caused by long-term GH deficiency [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTumor-related adverse reactions are a primary concern for parents, and this study revealed that malignant and unspecified tumor reactions accounted for 6.47% of the reports. Growth hormone is known to promote anabolic metabolism and cell mitosis, with IGF-1 exhibiting antiapoptotic properties, theoretically increasing the risk of tumorigenesis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, the National Cooperative Growth Study (NCGS) and the Pfizer International Growth Database (KIGS), along with the findings of most studies, suggest that growth hormone does not increase the risk of malignant tumors [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A recent article in The Lancet indicated that rhGH treatment does not affect overall cancer risk, although these studies have limitations [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The relatively high reporting rate of tumor-related adverse effects may be because individuals tend to be more sensitive to tumor-related health concerns than to other AEs, and patients in tumor-susceptible populations may already have existing tumors, potentially leading to secondary malignancies. The causal relationship between growth hormone and adverse tumor effects requires further research.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Analysis of Newly Suspected ADE Signals Related to Growth Hormone Medications\u003c/h2\u003e \u003cp\u003eAmong the top 20 reporting numbers and positive signal strengths based on preferred terms (PTs), 12 new suspected positive signals were identified that were not documented in the product labeling. These included growth retardation, obstructive sleep apnea syndrome, elbow deformities, pituitary cysts, and several abnormal laboratory findings. Research indicates that short-term risks for sleep apnea syndrome often occur in children with baseline obstructive symptoms or after upper respiratory infections. In contrast, growth hormone treatment does not appear to impact sleep-disordered breathing [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Growth hormone has the ability to break down fat, leading to various effects on lipid profiles; rhGH therapy tends to increase high-density lipoprotein (HDL) and decrease low-density lipoprotein (LDL) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Growth retardation could reflect individual differences in response to growth hormone therapy, with some children showing no significant effects or other underlying conditions causing stunted growth. Pituitary cysts and abnormal laboratory results may be related to the influence of growth hormone on endocrine function and metabolic growth, necessitating ongoing surveillance for new ADEs associated with growth hormone medications, particularly those that are novel and subtle.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Study Limitations\u003c/h2\u003e \u003cp\u003e① This study relied on the FAERS database to conduct signal detection for ADEs related to growth hormone medications in children. As a voluntary reporting system, it may contain duplicate reports, incomplete data, weak causal relationships, or even erroneous information. ②The reporting countries were predominantly the United States, Japan, and Colombia, with lower representation from other countries, introducing a potential racial bias and underscoring the need for more safety monitoring data across diverse populations. ③While the study indicated a higher reported incidence of benign, malignant, and unspecified tumors, this finding contradicts some existing research, suggesting the need for in-depth and long-term follow-up studies to determine any causal relationship between growth hormone and tumors.\u003c/p\u003e \u003cp\u003eGrowth hormone has been widely used in children, and for nearly 40 years, the safety data surrounding its use have been generally good. However, many issues persist, particularly regarding its long-term effects on children, thus highlighting the importance of rigorous monitoring and follow-up.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003cbr\u003e\u0026nbsp;Design of the study: YF; Data acquisition and analysis: WX; Draft the manuscript: YF, \u0026nbsp;WX; Manuscript revise and final version approval: YF, WX, JA B contributed equally to this work. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Suzhou Medical Engineering Collaborative Innovation Research Project (SZM2022015). Funders had no influence on the design of the study, the data collection and analysis, and the manuscript writing.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnonymized data were collected from a publicly available database (FAERS database, https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS. html), the need for ethics approval and consent was waived.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial or non-financial interests that are directly or indirectly related to the work submitted for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShaikh AA, Daftardar H, Alghamdi AA, et al. Effect of growth hormone treatment on children with idiopathic short stature (ISS), idiopathic growth hormone deficiency (IGHD), small for gestational age (SGA) and Turner syndrome (TS) in a tertiary care center. Acta Biomed. 2020; 91(1):29-40.\u003c/li\u003e\n\u003cli\u003eCollett‑Solberg PF, Ambler G, Backeljauw PF, et al. Diagnosis, genetics, and therapy of short stature in children: international perspective. Horm Res Paediatr. 2019; 92(1):1‑14.\u003c/li\u003e\n\u003cli\u003eRanke MB, Wit JM. Growth hormone-past, present and future. Nat Rev Endocrinol. 2018;14(5):285-300. \u003c/li\u003e\n\u003cli\u003eMcLenachan S, Lum MG, Waters MJ, et al. Growth hormone promotes proliferation of adult neurosphere cultures. Growth Horm IGF Res. 2009;19(3):212-8.\u003c/li\u003e\n\u003cli\u003eDrube J, Wan M, Bonthuis M, et al. Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease. Nat Rev Nephrol. 2019;15(9): 577-589.\u003c/li\u003e\n\u003cli\u003eBamba V, Kanakatti Shankar R. Approach to the Patient: Safety of Growth Hormone Replacement in Children and Adolescents. J Clin Endocrinol Metab. 2022;107(3):847-861. \u003c/li\u003e\n\u003cli\u003eTian X, Zheng S, Wang J, et al. Cardiac disorder-related adverse events for aryl hydrocarbon receptor agonists: a safety review. Expert Opin Drug Saf. 2022;21(12):1505-1510.\u003c/li\u003e\n\u003cli\u003eZhou CZ, Peng SK, Lin AQ, et al. Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. EClinical Medicine. 2023;59:101967. \u003c/li\u003e\n\u003cli\u003eBlethen SL, Allen DB, Graves D, et al. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. 1996;81(5):1704-1710.\u003c/li\u003e\n\u003cli\u003e Darendeliler F, Karagiannis G, Wilton P. Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. Horm Res. 2007; 68 (5):41-47.\u003c/li\u003e\n\u003cli\u003eNicholas A Tritos, Anne Klibanski. Effects of Growth Hormone on Bone. Prog Mol Biol Transl Sci. 2016;138:193-211.\u003c/li\u003e\n\u003cli\u003eBell J, Parker KL, Swinford RD, et al. Long-term safety of recombinanthuman growth hormone in children. J Clin Endocrinol Metab. 2010;95(1):167-177.\u003c/li\u003e\n\u003cli\u003eCutfield WS, Wilton P, Bennmarker H, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet. 2000;355(9204):610-613.\u003c/li\u003e\n\u003cli\u003eClayton PE, Cowell CT. Safety issues in children and adolescents during growth hormone therapy-a review. Growth Horm IGF Res. 2000;10(6):306-17.\u003c/li\u003e\n\u003cli\u003eSaenger P. Metabolic consequences of growth hormone treatment in paediatric practice. Horm Res. 2000;53(1):60-69. \u003c/li\u003e\n\u003cli\u003eGiovannucci E, Pollak M. Risk of cancer after growth-hormone treatment. Lancet. 2002; 360(9329):268-269.\u003c/li\u003e\n\u003cli\u003eWilton P, Mattsson AF, Darendeliler F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr. 2010;157(2):265-270.\u003c/li\u003e\n\u003cli\u003eDarendeliler F, Karagiannis G, Wilton P. Recurrence of brain tumours in patients treated with growth hormone: analysis of KIGS (Pfizer International Growth Database). Acta Paediatr. 2006;95(10):1284-90.\u003c/li\u003e\n\u003cli\u003eChild CJ, ZimmermannAG, Chrousos GP. Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program. J Clin Endocrinol Metab. 2019;104(2):379-389.\u003c/li\u003e\n\u003cli\u003eAllen DB, Rundle AC, Graves DA. Risk of leukemia in children treated with human growth hormone: review and reanalysis. J Pediatr. 1997;131(1 Pt 2):S32-6.\u003c/li\u003e\n\u003cli\u003eTuffli GA, Johanson A, Rundle AC. Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab. 1995;80(4):1416-22.\u003c/li\u003e\n\u003cli\u003eTidblad A, S\u0026auml;vendahl L. Childhood growth hormone treatment: challenges, opportunities, and considerations. Lancet Child Adolesc Health. 2024;8(8):600-610. \u003c/li\u003e\n\u003cli\u003eMiller JL, Shuster J, Theriaque D, et al. Sleep disordered breathing in infants with Prader-Willi syndrome during the first 6 weeks of growth hormone therapy: a pilot study. J Clin Sleep Med. 2009;5(5):448-453.\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":"Growth hormone, Children, FAERS, Adverse events, Signal mining","lastPublishedDoi":"10.21203/rs.3.rs-4895744/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4895744/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003eThis study aims to analyze the adverse event (ADE)related to the use of growth hormone drugs in children through mining the FDA Adverse Event Reporting System (FAERS) database, and provide references for clinical medication safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eData on children under 18 years of agefrom the FAERS database, covering the first quarter of 2004 to the first quarter of 2024, were extracted via the OpenVigil 2.1 tool. The reporting odds ratio (ROR) was employed to analyze adverse event signals related to growth hormones.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 10,487 ADE reports for children using growth hormones were obtained, revealing 381 risk signals across 20 organ systems. The top five system organ categories on the basis of the number of reports were general disorders and administration site conditions (29.82%), investigations (20.11%), musculoskeletal and connective tissue disorders (13.51%), nervous system disorders (13.15%), and neoplasms benign, malignant and unspecified (6.47%). Among the positive signals not mentioned in the product labeling, the top five included non-high-density lipoprotein cholesterol increased, blood 25-hydroxycholecalciferol decreased, blood urea nitrogen/creatinine ratio increased, globulins decreased, elbow deformity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe signal intensity associated with muscle, skeletal, and neurological abnormalities, as well as tumor occurrence in children via growth hormones, is relatively high. Continuous monitoring and enhanced medication oversight are necessary.\u003c/p\u003e","manuscriptTitle":"Signal Mining and Analysis of Adverse Events in Children Using Growth Hormones: A Real-World Study Based on FAERS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-11 04:27:53","doi":"10.21203/rs.3.rs-4895744/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":"87ba4768-c8f7-4b19-b332-89dd961f55f8","owner":[],"postedDate":"October 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-04T10:08:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-11 04:27:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4895744","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4895744","identity":"rs-4895744","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}