Background 背景
Recombinant human GH (rhGH) was first approved to treat children with growth hormone deficiency (GHD) by Food and Drug Administration (FDA) in the United States in 1985. The indications subsequently expanded to growth failure secondary to chronic renal failure, Turner syndrome, Prader‒Willi syndrome, small for gestational age (SGA) without catch-up growth, idiopathic short stature (ISS), SHOX deficiency, Noonan syndrome and so on [1]. The efficacy and the safety of rhGH have been proven in randomized controlled trials (RCTs), which are considered the highest level of evidences in clinical practice. However, due to the strict criteria and short observational time, RCTs could not fully reflect the reality of rhGH, especially in terms of safety [2].
重组人生长激素（rhGH）于 1985 年首次获得美国食品药品监督管理局（FDA）批准，用于治疗患有生长激素缺乏症（GHD）的儿童。随后，适应症扩大到慢性肾功能衰竭引起的生长迟缓、特纳综合征、普拉德-威利综合征、未追赶生长的早产儿（SGA）、特发性矮小症（ISS）、SHOX 缺乏症、诺南综合征等[ 1 ]。rhGH 的有效性和安全性已在随机对照试验（RCTs）中得到证实，这些试验被认为是临床实践中最高的证据水平。然而，由于严格的纳入标准和较短的观察时间，RCTs 无法完全反映 rhGH 的现实情况，特别是在安全性方面[ 2 ]。
Real-world evidences (RWEs) have become increasingly important in clinical practice. They are based on observational data from the daily medical world, representing the real situation in clinical practice [3]. RWEs are regarded to be complementary to RCTs. For example, RCTs have advantages in evaluating the efficacy of a drug, while RWEs can focus on the epidemiology, effectiveness, safety, or costs of treatments [4]. Since rhGH has been used in short children for almost 4 decades, numerous clinical information has been collected from hospital-based clinical systems, insurance company records, as well as post-marketing databases established and managed by pharmaceutical industries.
真实世界证据（RWEs）在临床实践中变得越来越重要。它们基于日常医疗世界的观察性数据，代表了临床实践中的实际情况[ 3 ]。RWEs 被认为是对随机对照试验（RCTs）的补充。例如，RCTs 在评估药物疗效方面具有优势，而 RWEs 可以关注治疗的人口学、有效性、安全性或成本[ 4 ]。由于重组人生长激素（rhGH）几乎已经用于矮小儿童近 40 年，从基于医院的临床系统、保险公司记录以及由制药行业建立和管理的上市后数据库中收集了大量的临床信息。
There are several large long-term real-world databases in the world. The Kabi/Pfizer International Growth Database (KIGS), which was established in 1987, was a large international observational database to monitor the long-term clinical outcomes and safety in children treated with Genotropin® (Pfizer, USA) [5]. The NordiNet International Outcome Study (ISO) and American Norditropin Studies: Web-Enabled Research (ANSWER) Program were non-interventional, multicenter registry studies monitoring the long-term outcomes of Norditropin® (NovoNordisk, Denmark). The NordiNet IOS was ongoing from 2006 to 2016 across 22 European and Middle Eastern countries, while the ANSWER Program operated from 2002 to 2016 in the United States [6]. The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) sponsored by Eli Lilly and Company (USA), was conducted in 30 countries between 1999 and 2015. It included not only patients treated with rhGH, but also a small portion of untreated patients [7]. Moreover, the large cross-European cohort, the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) established in 2009, conducted the study of rhGH-treated patients with follow-up and analysis independent from the pharmaceutical industry [8].
全球存在多个大型长期真实世界数据库。成立于 1987 年的卡比/辉瑞国际生长数据库（KIGS）是一个大型国际观察性数据库，用于监测接受 Genotropin®（辉瑞，美国）治疗儿童的长期临床结果和安全状况[ 5 ]。NordiNet 国际结局研究（ISO）和美国诺迪特普林研究：网络化研究（ANSWER）计划是非干预性多中心登记研究，监测诺迪特普林®（诺和诺德，丹麦）的长期结局。NordiNet IOS 从 2006 年至 2016 年在 22 个欧洲和中东国家进行，而 ANSWER 计划从 2002 年至 2016 年在美国运行[ 6 ]。由艾利·利利公司（美国）赞助的遗传学和神经内分泌学矮身材国际研究（GeNeSIS）在 1999 年至 2015 年间的 30 个国家进行。该研究不仅包括接受重组人生长激素（rhGH）治疗的病人，还包括一小部分未接受治疗的病人[ 7 ]。 此外，2009 年建立的、涵盖整个欧洲的大型队列研究——欧洲生长激素治疗的 安全性和适宜性（SAGhE）研究，对接受 rhGH 治疗的患者的随访和分析独立于制药行业[ 8 ]。
Over the past few years, there have been an upsurge of publications based on large long-term observational studies focusing on the safety of childhood rhGH treatment. We aimed to summarize the RWEs of rhGH treatment in children and discuss possible directions in the future.
近年来，基于大型长期观察性研究，关注儿童重组人生长激素（rhGH）治疗安全性的出版物数量激增。我们旨在总结儿童 rhGH 治疗的真实世界证据（RWEs），并讨论未来的可能方向。
Cancer risk 癌症风险
The correlation between growth hormone (GH) excess and cancer is controversial. Evidence from patients with acromegaly has suggested a relationship between increased circulating GH levels and elevated risks of colorectal and thyroid cancer [9]. Moreover, the effector of rhGH, insulin-like growth factor 1 (IGF-1), was proved to be positively associated with increased risks of different cancers, such as thyroid, colorectal, breast and prostate cancer [10]. Thus, rhGH treatment has led to concerns regarding increased risks of cancers.
生长激素（GH）过剩与癌症之间的相关性存在争议。来自肢端肥大症患者的证据表明，循环中 GH 水平的升高与结直肠癌和甲状腺癌的升高风险之间存在关联[ 9 ]。此外，rhGH 的效应因子胰岛素样生长因子 1（IGF-1）已被证明与不同癌症（如甲状腺癌、结直肠癌、乳腺癌和前列腺癌）的升高风险呈正相关[ 10 ]。因此，rhGH 治疗引起了人们对癌症风险增加的关注。
The potential link between rhGH therapy and an increased risk of cancer in children was first reported in Japan in the 1980s that described the development of leukemia in children treated with GH. However, at least half of these patients had predisposing risk factors for leukemia, and the risk of leukemia was not increased in children without risk factors. In 2002, a study of 1,848 patients treated with GH during childhood and early adulthood reported increased risks of colorectal cancer and Hodgkin lymphoma, but the absolute number of cases was extremely low.
重组人生长激素治疗与儿童癌症风险增加之间的潜在联系最早在 20 世纪 80 年代的日本被报道，描述了接受生长激素治疗的儿童发生白血病的情况。然而，至少有一半的这些患者有白血病易感风险因素，且没有风险因素的儿童白血病风险并未增加。2002 年，一项对 1,848 名在儿童和青少年早期接受生长激素治疗的患者的调查显示，结直肠癌和霍奇金淋巴瘤的风险增加，但病例绝对数量极低。
Since then, large observational real-world studies have been conducted to investigate the risk of cancer in rhGH-treated children. Most of the studies reported no increased risk of cancer in patients without underlying risk factors [5, 11]. The Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) cohort recruited 23,984 patients treated with rhGH in childhood were recruited for different reasons. The final results were published in 2017. The average time of follow-up for cancer incidence was 14.8 years per patient, and the mean age at the end of follow-up was 25.8 years. The results revealed that the risk of cancer was significantly increased in patients with previously diagnosed cancer. The standardized incidence ratio (SIR) was 1.4 with a 95% confidence interval (CI) ranging from 1.1 to 1.9. The overall risk of cancer was not increased in patients with growth failure only. However, for patients with other diseases, such as chronic renal diseases and Turner syndrome, the risks of bone and bladder cancer were significantly increased. Additionally, cancer risk was unrelated to the duration or cumulative dose of rhGH treatment, but for patients with previous cancer, the mortality risk of cancer increased significantly with increased doses of rhGH [12].
自那时起，已经进行了大量的大型观察性真实世界研究，以调查 rhGH 治疗儿童患癌症的风险。大多数研究报道，在没有潜在风险因素的病人中没有增加癌症风险[ 5 ， 11 ]。欧洲生长激素治疗的安全性和适宜性（SAGhE）队列招募了 23,984 名在儿童时期接受 rhGH 治疗的病人，他们因不同原因被招募。最终结果于 2017 年发表。每位患者的癌症发病率随访平均时间为 14.8 年，随访结束时的平均年龄为 25.8 岁。结果显示，以前诊断出癌症的患者的癌症风险显著增加。标准化发病率比（SIR）为 1.4，95%置信区间（CI）为 1.1 至 1.9。仅生长失败的患者的总体癌症风险没有增加。然而，对于其他疾病的患者，如慢性肾病和特纳综合征，骨癌和膀胱癌的风险显著增加。 此外，癌症风险与 rhGH 治疗的持续时间或累积剂量无关，但对于既往有癌症病史的患者，随着 rhGH 剂量的增加，癌症的死亡率风险显著增加[ 12 ]。
Most recently, a study from Sweden investigated the risk of neoplastic events of rhGH treatment during childhood in more than 3400 patients with GHD, SGA and ISS compared to healthy controls. The patients were followed for up to 35 years, with a median follow-up time of 19.8 years. The results showed that in early to mid-adulthood, a moderately increased risk for neoplastic events was observed in patients treated with rhGH, but no elevated risk of malignant neoplastic events was found. Additionally, a longer treatment duration, but not the mean or cumulative dose, was associated with an increased risk of neoplastic events [13].
最近，一项来自瑞典的研究调查了与 GHD、SGA 和 ISS 相关的 3400 多名儿童患者接受 rhGH 治疗期间发生肿瘤事件的风险，并与健康对照组进行了比较。患者随访时间最长可达 35 年，中位随访时间为 19.8 年。结果显示，在成年早期至中期，接受 rhGH 治疗的患者观察到肿瘤事件的风险略有增加，但未发现恶性肿瘤事件的风险升高。此外，治疗持续时间较长与肿瘤事件的风险增加相关，但并非平均剂量或累积剂量。
Thus far, according to the available reports, rhGH treatment in childhood does not appear to increase the risk of cancer in early adulthood for patients with low risk. Nevertheless, more high-quality studies with long observational times are needed to confirm these conclusions. More importantly, there is a shortage of high-quality evidence regarding the cancer risk associated with rhGH treatment in patients who have predisposing factors for cancer.
截至目前，根据现有报告，儿童时期使用重组人生长激素（rhGH）治疗似乎不会增加低风险患者成年早期患癌症的风险。然而，仍需要更多高质量、长期观察的研究来证实这些结论。更重要的是，关于 rhGH 治疗与具有癌症易感因素的患者的癌症风险相关的高质量证据仍然不足。
Cardiovascular risk 心血管风险
The GH/IGF-1 axis plays an important role in the cardiovascular system. Both GHD and excessive GH secretion can lead to an increased risk of cardiovascular diseases [14]. The underlying mechanisms involve direct effects of GH on endothelial function, as well as the indirect regulation of lipid and glucose metabolism [15].
生长激素/IGF-1 轴在心血管系统中发挥着重要作用。生长激素缺乏症和生长激素分泌过多都可能增加心血管疾病的风险[参考文献 0]。其潜在机制包括生长激素对内皮功能的直接影响，以及间接调节脂质和葡萄糖代谢[参考文献 1]。
The concern regarding the cardiovascular risk associated with pediatric treatment with rhGH was first raised in 2012 by the French subgroup of SAGhE. In the French subgroup, a total of 6928 children with GHD, ISS, neurosecretory dysfunction and SGA were recruited. The mean follow-up time was 17.3 years. The results revealed a significant increase in mortality due to diseases of the circulatory system or subarachnoid or intracerebral hemorrhage in patients treated with rhGH compared with the general French population [16, 17]. However, the subgroups of Belgium, Netherlands and Sweden from the same SAGhE cohorts did not observe the increased mortality from cardiovascular or cerebrovascular diseases [18].
关于使用重组人生长激素（rhGH）进行儿童治疗的 cardiovascular 风险的担忧，最早于 2012 年由 SAGhE 的法国小组提出。在法国小组中，共招募了 6928 名患有 GHD、ISS、神经分泌功能障碍和 SGA 的儿童。平均随访时间为 17.3 年。结果显示，与普通法国人群相比，接受 rhGH 治疗的患者因循环系统疾病或蛛网膜下腔或颅内出血导致的死亡率显著增加 [ 16 , 17 ]。然而，来自同一 SAGhE 系列的比利时、荷兰和瑞典的小组并未观察到心血管或脑血管疾病死亡率增加 [ 18 ]。
An observational study from Sweden investigated the association of childhood GH treatment with long-term cardiovascular diseases and the result was published in 2020. A total of 3408 patients with GHD, SGA, or ISS and 50,036 healthy controls were followed up, with a median follow-up time of 14.9 years. It showed that rhGH treatment during childhood in patients with GHD, SGA, or ISS was associated with increased risks of cardiovascular events in early adulthood, particularly in women. The hazard ratio (HR) for such events was 1.69 (95% CI 1.30-2.19), and the risk was particularly high in females with an HR of 2.05 (95% CI 1.31-3.20). Additionally, longer duration of rhGH treatment and total cumulative dose were related with higher risks for overall cardiovascular diseases [19].
瑞典的一项观察性研究调查了儿童生长激素治疗与长期心血管疾病之间的关系，该研究结果于 2020 年发表。共对 3408 名患有 GHD、SGA 或 ISS 的患者和 50,036 名健康对照者进行了随访，中位随访时间为 14.9 年。研究显示，在 GHD、SGA 或 ISS 患者中，儿童期接受 rhGH 治疗与成年早期心血管事件的风险增加有关，尤其是在女性中。此类事件的风险比（HR）为 1.69（95% CI 1.30-2.19），女性的风险尤其高，HR 为 2.05（95% CI 1.31-3.20）。此外，rhGH 治疗持续时间更长和总累积剂量与整体心血管疾病风险增加相关[ 19 ]。
To analyze the effect of childhood rhGH treatment on cardiovascular risk in SGA patients, a study from Netherlands longitudinally investigated the metabolic and cardiovascular health markers of adults born SGA during the 12 years of follow-up after the cessation of rhGH treatment. Comparison groups included adults born SGA with persistent short stature (SGA-S), adults born SGA and previously treated with growth hormone (SGA-GH), adults born SGA with spontaneous catch-up growth (SGA-CU) and adults born appropriate for gestational age (AGA). The results revealed that at approximately 30 years of age, SGA-GH adults had metabolic and cardiovascular health profiles similar to those of untreated adults born SGA or AGA. However, the sample sizes were small for the groups, as 167 SGA-GH patients, 50 SGA-S patients, 77 SGA-CU patients and 92 AGA adults were recruited for the study [20].
为了分析儿童 rhGH 治疗对 SGA 患者心血管风险的影响，荷兰的一项纵向研究调查了在 rhGH 治疗停止后 12 年随访期间出生的 SGA 成年人的代谢和心血管健康指标。比较组包括出生时 SGA 且持续矮身材的成年人（SGA-S）、出生时 SGA 且以前接受过生长激素治疗的成年人（SGA-GH）、出生时 SGA 且自发追赶生长的成年人（SGA-CU）和出生时孕周合适的成年人（AGA）。结果显示，大约 30 岁时，SGA-GH 成年人的代谢和心血管健康状况与未治疗的 SGA 或 AGA 成年人相似。然而，由于招募了 167 名 SGA-GH 患者、50 名 SGA-S 患者、77 名 SGA-CU 患者和 92 名 AGA 成年人，因此各组样本量较小[ 20 ]。
Thus, the effect of rhGH treatment in childhood on long-term cardiovascular risk is not clear. The inconsistency of the conclusions could be related to the heterogeneity of the studies, as well as the complexity of the confounders. Although the patients were followed up for more than 10 years, they were still young for the onset of cardiovascular disease. Noteworthy, the risk of cardiovascular disease varies among patients with different causes of short stature. For example, GHD patients without treatments have an increased risk of cardiovascular disease, and rhGH treatment was believed to improve cardiovascular risk in GHD patients [15]. Moreover, patients with SGA, Turner syndrome or Noonan syndrome have a greater risk of cardiovascular diseases [20–22]. The risk in patients with different causes should be assessed separately, and appropriate untreated groups should be recruited for comparison.
因此，儿童时期 rhGH 治疗对长期心血管风险的影响尚不明确。结论的不一致性可能与研究的异质性和混杂因素的复杂性有关。尽管患者被随访了 10 多年，但他们对于心血管疾病的发生来说仍然年轻。值得注意的是，不同原因矮小患者的心血管疾病风险存在差异。例如，未接受治疗的 GHD 患者心血管疾病风险增加，rhGH 治疗被认为可以改善 GHD 患者的心血管风险[ 15 ]。此外，SGA、特纳综合征或诺南综合征患者心血管疾病风险更高[ 20 – 22 ]。不同原因患者的风险应分别评估，并应招募适当的未治疗组进行比较。
Diabetes risk 糖尿病风险
GH inhibits the uptake and oxidation of glucose, increases gluconeogenesis and reduces insulin sensitivity. It is acknowledged as a key counter-regulatory hormone to insulin, and the propensity of GH to induce diabetes is further substantiated by the high prevalence of diabetes in patients with acromegaly. However, the impact of rhGH administration on overall glucose homeostasis is complex, partly due to the glucose-lowering influence of IGF-1[23].
GH 抑制葡萄糖的摄取和氧化，增加糖异生并降低胰岛素敏感性。它被认为是胰岛素的关键对抗调节激素，GH 诱导糖尿病的倾向通过肢端肥大症患者中糖尿病的高发病率进一步得到证实。然而，rhGH 对整体葡萄糖稳态的影响复杂，部分原因是 IGF-1 的降糖作用[ 23 ]。
In 2000, the Pharmacia and Upjohn International Growth Study (KIGS) study suggested a sixfold increase in the incidence of type 2 diabetes among children treated with rhGH, whereas the incidence of type 1 diabetes did not increase. Furthermore, the alteration in glucose metabolism persisted even after the discontinuation of rhGH [24]. However, the French SAGhE study, revealed no difference in the prevalence of diabetes between rhGH-treated patients with GHD, ISS, or SGA and the general population [25].
2000 年，辉瑞和优宁维国际生长研究（KIGS）研究指出，接受重组人生长激素（rhGH）治疗儿童的 2 型糖尿病发病率增加了六倍，而 1 型糖尿病的发病率没有增加。此外，即使在停止使用 rhGH 后，血糖代谢的改变仍然持续存在[ 24 ]。然而，法国 SAGhE 研究显示，接受 rhGH 治疗的 GHD、ISS 或 SGA 患者与普通人群的糖尿病患病率没有差异[ 25 ]。
A report based on Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS), an open-label, multinational, observational, postauthorization safety study sponsored by Eli Lilly and Co. (Indianapolis, IN), was established in 1999. A report based on the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) analyzed the incidence of diabetes in rhGH-treated children. It included children treated with rhGH due to GHD, ISS, Turner syndrome, SGA, Prader–Willi syndrome, chronic renal insufficiency and so on. A total of 21,448 patients were included in the study, with a median follow-up time of 5.0 years. The results showed that the incidence of type 2 diabetes was higher in rhGH-treated children than that in the general population (SIR 3.77; 95% CI 2.24-5.96). Among the 18 patients who developed type 2 diabetes, 13 patients exhibited risk factors, including organic GHD, Turner syndrome, Prader–Willi syndrome, obesity, and preexisting insulin resistance or impaired glucose tolerance [7].
基于国际矮身材遗传学和神经内分泌学研究（GeNeSIS），这是一项由礼来公司（印第安纳波利斯，印第安纳州）赞助的开放标签、多国、授权后安全性观察研究，于 1999 年建立。基于国际矮身材遗传学和神经内分泌学研究（GeNeSIS）的报告分析了 rhGH 治疗儿童中糖尿病的发生率。它包括因 GHD、ISS、特纳综合征、SGA、普拉德-威利综合征、慢性肾衰竭等接受 rhGH 治疗的儿童。研究共纳入 21,448 名患者，中位随访时间为 5.0 年。结果显示，rhGH 治疗儿童中 2 型糖尿病的发生率高于普通人群（SIR 3.77；95% CI 2.24-5.96）。在 18 名发展为 2 型糖尿病的患者中，13 名患者表现出风险因素，包括有机性 GHD、特纳综合征、普拉德-威利综合征、肥胖以及先前的胰岛素抵抗或葡萄糖耐量受损[ 7 ]。
In general, rhGH treatment appears to be associated with an increased risk of type 2 diabetes in children with susceptible factors. However, owing to the absence of the untreated control group, the precise effects of rhGH on glucose metabolism need to be further investigated.
总的来说，重组人生长激素（rhGH）治疗似乎与易感因素儿童患 2 型糖尿病的风险增加有关。然而，由于缺乏未接受治疗的控制组，rhGH 对葡萄糖代谢的精确影响需要进一步研究。
Mortality risk 死亡率风险
In 2012, the an analysis of the French subgroup of SAGhE revealed increased all-cause mortality, as well as mortality due to bone tumors and diseases of the circulatory system or subarachnoid or intracerebral hemorrhage [16]. However, the findings from the subgroup of Belgium, Netherlands and Sweden from the same SAGhE cohorts did not support these findings [18].
2012 年，对 SAGhE 法国子组的分析显示，全因死亡率以及因骨肿瘤和循环系统疾病或蛛网膜下腔或颅内出血导致的死亡率有所增加[ 16 ]。然而，来自同一 SAGhE 队列的比利时、荷兰和瑞典子组的发现并不支持这些结果[ 18 ]。
The full analysis of the entire dataset of the SAGhE cohort was reported in 2020. The cohort included 24,232 patients who were treated with rhGH during childhood, with up to 25 years of follow-up. The results indicated that all-cause mortality was not significantly increased in low-risk patients with GHD or ISS. In patients at moderate or high risk, such as those with clinically defined syndromes or pre-existing tumors, mortality was increased compared with in the general population. The standardized mortality ratio (SMR) was 3.8 (95% CI 3.3-4.4) and 17.1 (95% CI 15.6-18.7) for patients with moderate or high risk respectively. Additionally, mortality was not associated with the mean daily or cumulative dose of rhGH. This finding suggested that the increased mortality in patients with risk factors may not be related to rhGH treatment but may be due to the underlying diseases [26].
2020 年报道了 SAGhE 队列整个数据集的全面分析。该队列包括 24,232 名在儿童时期接受 rhGH 治疗的病人，随访时间最长可达 25 年。结果显示，GHD 或 ISS 的低风险患者全因死亡率没有显著增加。在中等或高风险患者中，如临床定义的综合征或既往肿瘤患者，死亡率与普通人群相比有所增加。中等或高风险患者的标准化死亡率比（SMR）分别为 3.8（95% CI 3.3-4.4）和 17.1（95% CI 15.6-18.7）。此外，死亡率与 rhGH 的平均每日剂量或累积剂量无关。这一发现表明，具有风险因素的患者死亡率增加可能与 rhGH 治疗无关，而可能是由于潜在疾病[ 26 ]。
A study published in 2021 collected data from the NordiNet International Outcome Study (2006–2016, Europe) and the ANSWER Program (2002–2016, USA). In total, 37 702 patients were included in the study, with up to 10 years of follow-up. The patients were classified into 3 mortality risk groups on the basis of primary diagnosis. As reported, no increased risk of mortality was found in any risk group [6].
2021 年发表的一项研究收集了来自 NordiNet 国际结局研究（2006-2016 年，欧洲）和 ANSWER 项目（2002-2016 年，美国）的数据。总共纳入了 37,702 名患者，随访时间最长可达 10 年。根据主要诊断，患者被分为 3 个死亡风险组。据报道，在任何风险组中都没有发现死亡风险增加[ 6 ]。
Overall, rhGH treatment does not seem to increase mortality risk in patients at low risk, but continued long-term surveillance is still needed to confirm this conclusion. Moreover, the mortality risk in patients with underlying disease should be further assessed.
总体而言，重组人生长激素（rhGH）治疗似乎不会增加低风险患者的死亡率风险，但仍需持续长期监测以确认这一结论。此外，应进一步评估患有潜在疾病患者的死亡率风险。
Future directions 未来方向
Despite the growing number of real-world studies on the long-term safety of childhood rhGH treatment, there is notable heterogeneity in the methodological rigor and quality of these studies. Owing to the nature of long-term observational studies, issues such as the heterogeneity of the study populations, the presence of confounding factors, the integrity of the data and attrition rates can undermine the robustness and validity of the study outcomes. Therefore, the implementation of rigorous inclusion and exclusion criteria, standardized data collection procedures, the mitigation of confounding factors, and an adequately sized sample are instrumental in enhancing the quality of the research. Furthermore, the complexity of the data necessitates the involvement of professional statisticians and epidemiologists to guarantee the application of robust methodology, as well as accurate analysis and interpretation.
尽管关于儿童生长激素治疗长期安全性的真实世界研究数量不断增加，但这些研究在方法论的严谨性和质量上存在显著异质性。由于长期观察性研究的性质，研究人群的异质性、混杂因素的影响、数据的完整性和脱落率等问题可能会削弱研究结果的稳健性和有效性。因此，实施严格的纳入和排除标准、标准化的数据收集程序、混杂因素的缓解以及足够大的样本量对于提高研究质量至关重要。此外，数据的复杂性需要专业统计学家和流行病学家的参与，以确保应用稳健的方法，以及准确的分析和解释。
Regarding the long-term safety of rhGH treatment, the durations of follow-up in the studies were still short, particularly with respect to cancer and cardiovascular risks. Owing to the exceptionally low incidence of events, such as cancer and death, the outcomes of the statistical analyses lack reliability. Thus, extended follow-up times and expanded sample sizes are essential for achieving robust RWE in subsequent research endeavors. Moreover, patients with different etiologies of short stature, accompanying diseases and predisposing factors are subject to varying levels of risk for clinical conditions, such as cancer, cardiovascular disease and diabetes. In this circumstance, an untreated control group would be preferable for comparison over a healthy control group. Information on confounding factors, including familial history, genetic background, environmental exposure, and lifestyle, should be meticulously collected and analyzed. Additionally, the long-term safety of childhood rhGH therapy related to the dosage and duration of treatment needs to be further investigated. In patients with rare diseases, such as RASopathies, chromosomal breakage syndromes or DNA repair disorders, the long-term safety of rhGH therapy should also be exhaustively explored.
关于重组人生长激素（rhGH）治疗的长期安全性，研究中随访的持续时间仍然较短，尤其是在癌症和心血管风险方面。由于癌症和死亡等事件的发生率异常低，统计分析的结果缺乏可靠性。因此，为了在后续的研究中实现稳健的真实世界证据（RWE），延长随访时间和扩大样本量是必要的。此外，不同病因的矮小症患者、伴随疾病和易感因素的临床状况（如癌症、心血管疾病和糖尿病）的风险水平各不相同。在这种情况下，与一个健康对照组相比，一个未经治疗的对照组更适合进行比较。应仔细收集和分析有关混杂因素的信息，包括家族史、遗传背景、环境暴露和生活方式。此外，还需要进一步研究儿童 rhGH 治疗与剂量和持续时间相关的长期安全性。 在罕见病患者中，如 RASopathies、染色体断裂综合征或 DNA 修复障碍患者，rhGH 疗法的长期安全性也应彻底探讨。
In conclusion, the long-term safety of childhood rhGH treatment seems to be established in patients at low risk, but long-term real-world studies with large sample sizes are essential for comprehensive validation. Furthermore, safety in patients with varying clinical conditions and confounding factors requires additional investigation.
总之，儿童生长激素治疗的长期安全性似乎已在低风险患者中得到证实，但进行大样本量的长期真实世界研究对于全面验证至关重要。此外，对于具有不同临床状况和混杂因素的患者，安全性需要进一步研究。
Author contributions 作者贡献
ZC: conceptualization and writing–drafting manuscripts. LY: conceptualization. LXP: conceptualization, writing–review and editing. All authors approved it for publication.
ZC：概念化和撰写稿件。LY：概念化。LXP：概念化、撰写-审阅和编辑。所有作者均批准了该稿件发表。
Funding 资助
None. 无。
Data availability 数据可用性
No datasets were generated or analyzed during the current study.
本研究期间未生成或分析任何数据集。
Declarations 声明
Conflict of interest 利益冲突
No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Author LXP is a member of the Editorial Board of World Journal of Pediatrics. The paper was handled by other editor and has undergone rigorous peer review process. Author LXP was not involved in the journal's review of, or decisions related to this manuscript.
未从与本文主题直接或间接相关的任何一方获得或将要获得任何财务或非财务利益。作者 LXP 是世界儿科杂志编委会成员。该论文由其他编辑处理，并经过严格的同行评审过程。作者 LXP 未参与该杂志对这篇论文的评审或与该稿件相关的决策。
Ethical approval 伦理批准
Not needed for this review article.
无需为此综述文章。
Footnotes 脚注
Publisher's Note 出版者的话
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
施普林格自然对已发表地图中的司法管辖权声明和机构隶属关系保持中立。
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Associated Data 相关数据
This section collects any data citations, data availability statements, or supplementary materials included in this article.
本节收集了本文中包含的任何数据引用、数据可用性声明或补充材料。
Data Availability Statement
数据可用性声明
No datasets were generated or analyzed during the current study.
本研究期间未生成或分析任何数据集。