Impact of body mass index on growth hormone stimulation tests in children and adolescents: a systematic review and meta-analysis

Peak stimulated growth hormone (GH) levels are known to decrease with increasing body mass index (BMI), possibly leading to overdiagnosis of GH deficiency (GHD) in children with overweight and obesity. However, current guidelines do not guide how to interpret the peak GH values of these children. This systematic review and meta-analysis aimed to study the effect of the BMI standard deviation score (SDS) on stimulated peak GH values in children, to identify potential moderators of this association, and to quantify the extent to which peak GH values in children with obesity are decreased. This systematic review was performed by the PRISMA guidelines. Medline, Embase, Cochrane, Web of Science, and Google Scholar databases were searched for studies reporting the impact of weight status on peak GH in children. Where possible, individual participant data was extracted and/or obtained from authors. Quality and risk of bias were evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) checklists. The primary outcome was the association between peak GH values and BMI SDS. The pooled correlation coefficient r, 95% confidence interval (CI), and heterogeneity statistic I2 were calculated under a multilevel, random-effects model. In addition, exploratory moderator analyses and meta-regressions were performed to investigate the effects of sex, pubertal status, presence of syndromic obesity, mean age and mean BMI SDS on the study level. For the individual participant dataset, linear mixed-models regression analysis was performed with BMI SDS as the predictor and ln(peak GH) as the outcome, accounting for the different studies and GH stimulation agents used. In total, 58 studies were included, providing data on n = 5135 children (576 with individual participant data). Thirty-six (62%) studies had high, 19 (33%) medium, and 3 (5%) low risks of bias. Across all studies, a pooled r of −0.32 (95% CI −0.41 to −0.23, n = 2434 patients from k = 29 subcohorts, I2 = 75.2%) was found. In meta-regressions, larger proportions of males included were associated with weaker negative correlations (p = 0.04). Pubertal status, presence of syndromic obesity, mean age, and mean BMI SDS did not moderate the pooled r (all p > 0.05). Individual participant data analysis revealed a beta of −0.123 (95% CI −0.160 to −0.086, p

已知刺激后生长激素（growth hormone, GH）峰值水平随体重指数（body mass index, BMI）升高而降低，这可能导致超重与肥胖儿童被过度诊断为生长激素缺乏症（growth hormone deficiency, GHD）。然而，当前指南并未针对此类儿童的GH峰值解读提供指导。本系统评价与荟萃分析旨在探究BMI标准差评分（standard deviation score, SDS）对儿童刺激后GH峰值的影响，识别该关联的潜在调节变量，并量化肥胖儿童GH峰值的降低幅度。
本系统评价严格遵循PRISMA指南开展。研究检索了Medline、Embase、Cochrane、Web of Science及Google Scholar数据库，筛选报道体重状态对儿童GH峰值影响的相关研究。尽可能提取了个体参与者数据，或直接向作者获取此类数据。采用苏格兰院校指南网络（Scottish Intercollegiate Guidelines Network, SIGN）量表评估研究质量与偏倚风险。
本研究的主要结局为GH峰值与BMI SDS之间的关联。采用多层随机效应模型计算合并相关系数r、95%置信区间（confidence interval, CI）及异质性统计量I²。此外，本研究开展了探索性调节变量分析与Meta回归，以探究性别、青春期状态、综合征性肥胖存在情况、平均年龄及平均BMI SDS在研究层面的影响。
针对个体参与者数据集，本研究以BMI SDS为预测变量、GH峰值的自然对数（ln(peak GH)）为结局变量，开展线性混合模型回归分析，同时纳入不同研究及所用GH刺激剂作为协变量。
最终共纳入58项研究，涵盖5135名儿童的数据（其中576名儿童拥有个体参与者数据）。36项（62%）研究存在高偏倚风险，19项（33%）为中等偏倚风险，3项（5%）为低偏倚风险。所有研究的合并相关系数r为-0.32（95%CI：-0.41~-0.23，纳入29个亚队列的2434名患者，I²=75.2%）。Meta回归分析显示，纳入男性的比例更高与负相关强度更弱相关（p=0.04）。青春期状态、综合征性肥胖存在情况、平均年龄及平均BMI SDS均未对合并相关系数r产生调节作用（所有p>0.05）。个体参与者数据分析显示，回归系数β为-0.123（95%CI：-0.160~-0.086，p