In this retrospective study, we comprehensively analyzed differences in endocrine stimulation tests performed in a pediatric endocrinology outpatient department between 2019 and 2020 to detect any effect of COVID-19 pandemic restrictions.
Overall, we found a reduction of 10% in tests and 8% in children evaluated between 2019 and 2020, which was not related to hospital policies, since endocrine stimulation tests were considered urgent admissions during COVID-19 lockdown and the available number of beds for investigations remained unchanged. The most significant detected changes were a reduction in tests to diagnose GHD (− 30% of patients diagnosed in 2020) and an increase in CPP diagnosis (+ 38%, mainly females).
Regarding the tests investigating GH secretion, we detected a striking reduction (− 35%) in tests performed in 2020, compared to 2019. This was sharply in contrast with a steady increase in referrals for growth issues that we reported from 2014 to 2018 in a previous study , even though the criteria – according to the Italian Medicines Agency (AIFA) – to perform stimulation tests were the same (i.e., height ≤ − 3 SD; or height ≤ − 2 SD + growth velocity per year ≤ − 1 DS for age and sex evaluated for at least 6 months or a reduction of height of 0.5 SD per year in children > 2 years of age; or height ≤ − 1.5 SD compared to target height and growth velocity per year ≤ − 2 SD or ≤ − 1.5 SD for two consecutive years; or growth velocity per year ≤ − 2 SD or ≤ − 1.5 SD after two consecutive years, even without short stature and after exclusion of other causes of failure to thrive; or malformations/lesions of hypothalamus/pituitary demonstrated at brain MRI) . Although this is the first study reporting a decrease of referrals for suspected GHD during 2020 lockdowns, our results align with previous reports addressing a delay of hospital care admissions and a reduction of 30–40% in visits during the COVID-19 pandemic [9, 10]. A possible explanation for the decrease in tests for suspected GHD is that well-child visits were canceled during the pandemics, removing a chance for family pediatricians to detect short stature and delayed growth. Moreover, families did not have the opportunity to compare their children with classmates (because of remote schooling and the absence of other social activities), missing possible deviations from the regular growth pattern to share with their family pediatricians. Although not considered in the present study, we have to contemplate that some families might have canceled their booked appointment because they feared going to the hospital during a pandemic or thought short stature was not an urgent issue. Since the rate of GHD among referred children was similar in the 2 years (30% in 2019, 35% in 2020) and coherent with previous data [1, 14] we probably missed 8 GHD diagnoses in 2020. Although these children might have been referred and eventually treated at a later stage, we know that the efficacy of treatment is increased if started at a younger age . Moreover, approximately 35% of the patients with GHD have an organic etiology, and a delay in such a diagnosis can be life-threatening .
On the other side, our study found a clinically meaningful increase in CPP diagnoses in girls (+ 16%) during 2020 compared to the same period in 2019. A “breast bud” appearance in a girl before the age of 8 years is always troublesome and easier to detect by families, even without comparisons with peers. Moreover, parents working from home might have increased the time spent with their children, detecting early pubertal changes more quickly. On the other hand, there was a decrease of 75% in CPP diagnosis in males. This reduction can be determined by the subtle finding of testicular enlargement (the earliest evidence of puberty in males) that patients and parents often go unnoticed and can be missed if well-child visits from family pediatricians are missed.
An increase in the incidence of CPP had already been reported years before the advent of the COVID-19 pandemic in several countries, including France (Gaspari L, et al. ), Korea (Kim SH et al., )and Denmark (Sømod ME, et al. ), but not Italy where both referrals for CPP  and new diagnosis of CPP (Stagi ) were stable during the previous 5 years.
Our findings of an increase of CPP during COVID-19 lockdown are in accordance with other two Italian reports: the first study found an increased incidence of newly diagnosed CPP in females with a faster rate of pubertal progression during COVID-19 pandemics compared to the same period, each year, from 2015 to 2019 ; similarly, in the second study, a rise in referrals for suspected precocious puberty was recorded in 2020 (+ 108% consultations compared to 2019) . Since the hypothesis of a direct effect of Sars-CoV2 as a trigger of puberty remains unlikely, these results seem to suggest a possible role of environmental factors on the early onset of puberty during COVID-19 pandemics .
Precocious pubertal timing is crucial, resulting in a child sexually mature at an emotionally and socially inappropriate age, thus leading to risk-taking behaviors as sexual relations and substance use . Genetics plays a significant role in CPP; however, environmental factors as obesity and adverse childhood experiences may influence pubertal development [24, 25]. Moreover, epidemiological studies in humans demonstrated that exposures to endocrine-disrupting compounds have pronounced effects on pubertal timing increasing an early onset of puberty . Since COVID-19 outbreak limitations forced children to home-schooling and sedentary lifestyle, a cross-sectional study found a change in dietary habits, with increased consumption of hypercaloric foods as pizza, bread, sweets, and more snacking, thus leading to overweight . Considering these observations, we hypothesized a possible association of increased overweight secondary to COVID-19 restrictions and early puberty. Interestingly, we found no increase in BMI SDS between early pubertal girls observed in 2020. Our results align with an Italian report on referrals for precocious puberty in 2020, where no significant differences in anthropometric parameters were found compared to 2019 . COVID-19 restrictions exposed children to e-learning and increased the use of screens. Stagi et al. found a more than doubled increase in time spent using electronic devices in children during the lockdown, hypothesizing its possible role in triggering puberty’s early onset and tempo .
A potential limitation of this study is based on data collected retrospectively from a single center; therefore, results may be related to the local population and did not allow further analysis on other contributing factors. On the other hand, to our knowledge, this is the first study that has simultaneously analyzed the features of pediatric endocrine stimulation tests as a whole during COVID-19 pandemics. Another limitation is the comparison between 2 years (2019 and 2020) only, while it could have been interesting to analyze data from the previous years, as well as it could be interesting to evaluate data in the following years to evaluate if the founded changes were part of a trend from the previous years or were limited to the lockdown restrictions or due to the change in everyday life during pandemic years.