Growth Hormone Treatment in SGA : More than meets the eye

Growth hormone (GH) treatment effectively induces catch-up growth and improves adult height in short children born small for gestational age (SGA). Besides this visual effect, GH treatment also has several other effects which occur inside the body. This doctoral thesis presents the effects of GH treatment, with or without additional gonadotropin-releasing hormone analog (GnRHa) treatment, on metabolic and cardiovascular risk factors. The effects of GnRHa treatment, in addition to GH treatment, on pubertal development are described. Further, the long-term effects of discontinuation of GH treatment are assessed in young adults born SGA. Finally, a new genetic cause for persistent short stature after SGA birth is revealed. The results presented in this thesis illustrate that there is more to GH treatment than meets the eye

Cerebral white matter hyperintensities in adults born small for gestational age at 12 years after cessation of childhood growth hormone treatment:a prospective cohort study including untreated controls

Background: Increased cerebrovascular morbidity was reported in adults born small for gestational age (SGA) who were treated with growth hormone (GH) during childhood compared to the general population. Yet, previous studies lacked an appropriate control group which is a major limitation. We prospectively studied cerebral white matter hyperintensities (WMHs) in adults born SGA at 12 years after cessation of childhood GH-treatment (SGA-GH), compared to appropriate controls. Methods: In this prospective cohort study, performed between May 2016 and December 2020, total WMHs, periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) were the primary outcomes of the study, they were qualitatively assessed using 3 Tesla (T) Magnetic Resonance Imaging (MRI) and scored using the Fazekas scale in SGA-GH adults and in 3 untreated control groups: adults born SGA with persistent short stature (SGA-S), adults born SGA with spontaneous catch-up growth to a normal height (SGA-CU) and adults born appropriate for gestational age with a normal height (AGA). Regression analyses were performed in the total cohort to evaluate the associations of GH-treatment and birth characteristics with WMHs. Findings: 297 adults were investigated (91 SGA-GH, 206 controls). Prevalence of total WMHs was 53.8% (95% CI 43.1–64.3) in SGA-GH, 40.5% (95% CI 25.6–56.7) in SGA-S, 73.9% (95% CI 61.9–83.7) in SGA-CU and 41.1% (95% CI 31.1–51.6) in AGA adults. No statistically significant differences in total WMHs, PVWMHs and DWMHs were found between SGA-GH compared to SGA-S and AGA adults. Highest prevalence of all type of WMHs was found in SGA-CU adults compared to all groups. Higher prevalence of total WMHs was associated with lower birth weight standard deviation score (SDS), but not with GH-treatment. Interpretation: Our findings suggest that GH-treatment in children born SGA has no negative impact on the prevalence of all type of WMHs at 12 years after GH cessation compared to appropriate controls. SGA-CU adults had the highest prevalence of all type of WMHs around age 30 years. Funding: Novo Nordisk.</p

Longitudinal Study on Metabolic Health in Adults SGA During 5 Years After GH With or Without 2 Years of GnRHa Treatment

BACKGROUND: In children born small for gestational age (SGA) with persistent short stature, 2 years of gonadotropin-releasing hormone analogue (GnRHa), in addition to long-term growth hormone (GH) treatment, can improve adult height. We assessed safety on metabolic and bone health of GnRHa/GH treatment during 5 years after cessation of GH. METHODS: A total of 363 young adults born SGA, previously treated with combined GnRHa/GH or GH-only, were followed for 5 years after attainment of adult height at GH cessation and 2 and 5 years thereafter. Data at 5 years after GH cessation, at age 21 years, were also compared with 145 age-matched adults born appropriate for gestational age (AGA). Frequently sampled intravenous glucose tolerance (FSIGT) tests were used to assess insulin sensitivity, acute insulin response, and β-cell function. Body composition and bone mineral density (BMD) was determined by dual-energy x-ray absorptiometry (DXA) scans. FINDINGS: In the GnRHa/GH and GH-only groups, fat mass increased during the 5 years after GH cessation, but the changes in FSIGT results, body composition, blood pressure, serum lipid levels, and BMD were similar in both groups. At age 21 years, the GnRHa/GH group had similar fat mass, FSIGT results, blood pressure, serum lipid levels and BMD-total body as the GH-only group and the AGA control group, a higher BMD-lumbar spine and lower lean body mass than the AGA control group. INTERPRETATION: This study during 5 years after GH cessation shows that addition of 2 years of GnRHa treatment to long-term GH treatment of children short in stature born SGA has no unfavorable effects on metabolic and bone health in early adulthood. CLINICAL TRIAL REGISTRATION: ISRCTN96883876, ISRCTN65230311 and ISRCTN18062389

Cerebral white matter hyperintensities in adults born small for gestational age at 12 years after cessation of childhood growth hormone treatment:a prospective cohort study including untreated controls

Background: Increased cerebrovascular morbidity was reported in adults born small for gestational age (SGA) who were treated with growth hormone (GH) during childhood compared to the general population. Yet, previous studies lacked an appropriate control group which is a major limitation. We prospectively studied cerebral white matter hyperintensities (WMHs) in adults born SGA at 12 years after cessation of childhood GH-treatment (SGA-GH), compared to appropriate controls. Methods: In this prospective cohort study, performed between May 2016 and December 2020, total WMHs, periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) were the primary outcomes of the study, they were qualitatively assessed using 3 Tesla (T) Magnetic Resonance Imaging (MRI) and scored using the Fazekas scale in SGA-GH adults and in 3 untreated control groups: adults born SGA with persistent short stature (SGA-S), adults born SGA with spontaneous catch-up growth to a normal height (SGA-CU) and adults born appropriate for gestational age with a normal height (AGA). Regression analyses were performed in the total cohort to evaluate the associations of GH-treatment and birth characteristics with WMHs. Findings: 297 adults were investigated (91 SGA-GH, 206 controls). Prevalence of total WMHs was 53.8% (95% CI 43.1–64.3) in SGA-GH, 40.5% (95% CI 25.6–56.7) in SGA-S, 73.9% (95% CI 61.9–83.7) in SGA-CU and 41.1% (95% CI 31.1–51.6) in AGA adults. No statistically significant differences in total WMHs, PVWMHs and DWMHs were found between SGA-GH compared to SGA-S and AGA adults. Highest prevalence of all type of WMHs was found in SGA-CU adults compared to all groups. Higher prevalence of total WMHs was associated with lower birth weight standard deviation score (SDS), but not with GH-treatment. Interpretation: Our findings suggest that GH-treatment in children born SGA has no negative impact on the prevalence of all type of WMHs at 12 years after GH cessation compared to appropriate controls. SGA-CU adults had the highest prevalence of all type of WMHs around age 30 years. Funding: Novo Nordisk.</p

Fat mass and fat-free mass track from infancy to childhood:New insights in body composition programming in early life

OBJECTIVE: Early life is a critical window for adiposity programming. This study investigated whether fat mass percentage (FM%), fat mass index (FMI), abdominal fat, and fat‐free mass (FFM) in early life track into childhood and whether there are sex differences and differences between infant feeding types. METHODS: Detailed body composition was longitudinally measured by air‐displacement plethysmography, dual‐energy x‐ray absorptiometry, and abdominal ultrasound in 224 healthy, term‐born children. Measurements were divided into tertiles. Odds ratios (OR) of remaining in the highest tertile of FM%, FMI, abdominal subcutaneous and visceral fat, and FFM index (FFMI) were calculated from early life to age 4 years. RESULTS: High FM% and FMI tracked from age 3 and 6 months to age 4 years (OR = 4.34 [p = 0.002] and OR = 6.54 [p < 0.001]). High subcutaneous abdominal fat tracked from age 6 months to age 4 years (OR = 2.30 [p = 0.012]). High FFMI tracked from age 1, 3, and 6 months to age 4 years (OR = 4.16 [p = 0.005], 3.71 [p = 0.004], and 3.36 [p = 0.019]). In non‐exclusively breastfed infants, high FM% tracked from early life to age 4 years, whereas this was not the case for exclusively breastfed infants. There was no tracking in visceral fat or sex differences. CONCLUSIONS: Infants with high FM%, FMI, subcutaneous abdominal fat, and FFMI in early life are likely to remain in the highest tertile at age 4 years. Exclusive breastfeeding for 3 months is potentially protective against having high FM% at age 4 years

International Consensus Guideline on Small for Gestational Age (SGA): Etiology and Management from Infancy to Early Adulthood

: This International Consensus Guideline was developed by experts in the field of SGA of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Besides, it presents long-term consequences of SGA birth and new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, and the metabolic and cardiovascular health of young adults born SGA after cessation of childhood-GH-treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardio-metabolic health profile in adulthood. Children born SGA with persistent short stature &lt; -2.5 SDS at age 2 years or &lt; -2 SDS at age of 3-4 years, should be referred for diagnostic work-up. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033-0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3-4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle