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.