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

Abstract

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 β-cell function (p=0·157 for the difference from growth hormone cessation to 12-year follow-up) and showed an increase in insulin sensitivity (p=0·002), fat mass (p<0·001), total cholesterol (p<0·001), and blood pressure (p<0·001). By around age 30 years, these parameters reached similar levels to those in SGA-S adults (insulin sensitivity p=0·242; fat mass p=0·449; total cholesterol p=0·616; systolic blood pressure p=0·523; diastolic blood pressure p=0·538). 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 44·67 kg [95% CI 43·54-45·80] in SGA-GH adults vs 47·65 kg [46·39-48·92] in adults born appropriate for gestational age) and higher concentrations of adverse serum lipids, such as cholesterol (4·75 mmol/L [4·55-4·95] vs 4·33 mmol/L [4·13-4·5]), which were present in all groups born SGA. Abdominal adiposity (visceral adipose tissue p=0·107; subcutaneous adipose tissue: p=0·244), liver fat fraction (p=0·104), and blood pressure (systolic blood pressure 0·927; diastolic blood pressure: 0·737) 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.

Funding: Novo Nordisk.