Childhood growth hormone treatment and metabolic and cardiovascular risk in adults born small for gestational age after growth hormone cessation in the Netherlands: a 12-year follow-up study

Background Childhood growth hormone treatment has been associated with increased cardiovascular mortality and morbidity in adults born small for gestational age (SGA) compared with the general population, but these risks have not been compared with untreated control groups. We aimed to investigate longitundinal metabolic and cardiovascular health in adults born SGA after cessation of growth hormone treatment. Methods We longitudinally investigated the metabolic and cardiovascular health profile of 167 adults born SGA and previously treated with growth hormone during the 12 years after growth hormone cessation. Metabolic and cardiovascular parameters were assessed with the frequently sampled intravenous glucose tolerance test, serum lipids and blood pressure were measured, body composition was determined by dual-energy x-ray absorptiometry, and visceral fat was measured by MRI. At approximately age 30 years, we compared the metabolic and cardiovascular health profile of adults born SGA and previously treated with growth hormone (SGA-GH) with 219 untreated adults: 127 born SGA with either persistent short stature (SGA-S) or spontaneous catch-up to typical adult stature (SGA-CU), and 92 born appropriate for gestational age. Findings During 12 years of follow-up, SGA-GH adults maintained normal ss-cell function (p=0 center dot 157 for the difference from growth hormone cessation to 12-year follow-up) and showed an increase in insulin sensitivity (p=0 center dot 002), fat mass (p < 0 center dot 001), total cholesterol (p < 0 center dot 001), and blood pressure (p < 0 center dot 001). By around age 30 years, these parameters reached similar levels to those in SGA-S adults (insulin sensitivity p=0 center dot 242; fat mass p=0 center dot 449; total cholesterol p=0 center dot 616; systolic blood pressure p=0 center dot 523; diastolic blood pressure p=0 center dot 538). By around age 30 years, SGA-GH adults also had similar metabolic and cardiovascular health parameters to adults born appropriate for gestational age, with the exception of lower lean body mass (estimated marginal mean 44 center dot 67 kg [95% CI 43 center dot 54-45 center dot 80] in SGA-GH adults vs 47 center dot 65 kg [46 center dot 39-48 center dot 92] in adults born appropriate for gestational age) and higher concentrations of adverse serum lipids, such as cholesterol (4 center dot 75 mmol/L [4 center dot 55-4 center dot 95] vs 4 center dot 33 mmol/L [4 center dot 13-4 center dot 5]), which were present in all groups born SGA. Abdominal adiposity (visceral adipose tissue p=0 center dot 107; subcutaneous adipose tissue: p=0 center dot 244), liver fat fraction (p=0 center dot 104), and blood pressure (systolic blood pressure 0 center dot 927; diastolic blood pressure: 0 center dot 737) were similar between SGA-GH adults and all control groups. Interpretation At approximately age 30 years, SGA-GH adults had a similar metabolic and cardiovascular health profile to untreated adults born SGA or appropriate for gestational age, indicating long-term metabolic and cardiovascular safety of growth hormone treatment for children born SGA with short stature.