Nicolette Arends

Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA)

Background  Epidemiological studies have shown that the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidaemia and a high body mass index (BMI), occurs more frequently among adults who were born with a low birth weight. Because insulin is thought to play a key role in the pathogenesis of this syndrome we investigated insulin sensitivity and risk factors for cardiovascular disease in short prepubertal children born small for gestational age (SGA).

GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial

background  To investigate in a group of short children born small for gestational age (SGA), the effects of 3 years of GH treatment vs. no treatment on bone age (BA), height and bone mineral density (BMD). Also, to evaluate the influence of the severity of growth retardation at start and the GH dose on the gain in height.

Food Intake of Children with Short Stature Born Small for Gestational Age before and during a Randomized GH Trial

Parents of short children born SGA often report that their children have a serious lack of appetite and a low food intake. In this study we investigated food intake, by using a standardized 7-day food questionnaire, in 88 short SGA children before start of GH treatment. The intake was compared with the recommended daily intake (RDI) of age-matched children. We also compared the food intake of GH-treated children (n = 62) with randomized controls (n = 26) after 1 year of GH treatment. In addition, we evaluated the effect of food intake and GH treatment on body composition and serum levels of IGF-I, IGFBP-3 and leptin. Our study shows that caloric intake, fat and carbohydrate intake of short SGA children aged 5.9 (1.6) years was significantly lower compared to the RDI for age-matched children. One year of GH treatment resulted in a significant increase of caloric, fat, carbohydrate and protein intake compared to baseline. Compared to randomized controls, caloric, carbohydrate and protein intake increased significantly after 1 year of GH treatment. Short SGA children had significantly lower SDS scores for LBM, fat mass, skinfold (SF) and BMI compared to age-matched references. They also had significantly lower serum IGF-I, IGFBP-3 and leptin levels. GH treatment resulted in a significant increase of height, LBM, BMI, IGF-I and IGFBP-3 SDS and a significant decrease of SF SDS and leptin SDS. In conclusion, our study shows that short SGA children have indeed a lower food intake than age-matched controls. During GH treatment the food intake increased significantly compared to baseline in contrast to the randomized control group.

Effects of Growth Hormone Treatment on Cognitive Function and Head Circumference in Children Born Small for Gestational Age

Short stature is not the only problem faced by children born small for gestational age (SGA). Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence and behavioural problems. This paper summarizes the results of a randomized, double-blind, growth hormone (GH) dose-response study (1 or 2 mg/m2/day [∼0.035 or 0.07 mg/kg/day]) on growth, intelligence quotient (IQ) and psychosocial functioning in 79 children born SGA at the start, and after 2 and 8 years of GH therapy, and addresses the associations with head circumference. Mean age at start of therapy was 7.4 years; mean duration of GH treatment was 8.0 years. In 2001, 91% of children born SGA had reached a normal height (> –2.0 standard deviation score [SDS]). Block-design s-score (Performal IQ) and Total IQ score increased (p< 0.001 for both indices) from scores significantly lower than those of Dutch peers at the start of therapy (p < 0.001) to scores that were comparable to those of Dutch peers in 2001. Vocabulary s-score (Verbal IQ) was normal at the start of therapy and remained so over time. Externalizing Problem Behaviour SDS and Total Problem Behaviour SDS improved during GH therapy (p < 0.01–0.05) to scores comparable to those of Dutch peers. Internalizing Problem Behaviour SDS was comparable to that of Dutch peers at the start of therapy and remained so, whereas Self-Perception improved from the start of GH therapy until 2001 (p < 0.001), when it reached normal scores. Head circumference SDS at the start of GH therapy and head growth during GH therapy were positively related to all IQ scores (p < 0.01), whereas neither were related to height SDS at the start of, or to its improvement during, GH therapy. A significant improvement in height and head circumference in children born SGA was seen after only 3 years of GH therapy, in contrast to randomized SGA controls. In conclusion, most children born SGA showed a normalization of height during GH therapy and, in parallel to this, a significant improvement in Performal IQ and Total IQ. In addition, problem behaviour and self-perception improved significantly. Interestingly, Performal, Verbal and Total IQ scores were positively related to head circumference, both at the start of, and during, GH therapy; head circumference increased in GH-treated children born SGA, but not in untreated SGA controls. These results are encouraging but also warrant confirmational studies and further investigations into the effects of GH on the central nervous system.

Head Circumference and Body Proportions Before and During Growth Hormone Treatment in Short Children Who Were Born Small for Gestational Age

Objective. Although short children who were born small for gestational age (SGA) seem to have normal body proportions, objective data both before and during growth hormone (GH) treatment are very limited. Therefore, we investigated in a large group of short children who were born SGA the effects of GH treatment versus no treatment on head circumference (HC) and body proportions. Furthermore, we studied differences in linear growth and HC between SGA children who were born with a low birth length and birth weight (SGAL+W) and SGA children who were born with a low birth length only (SGAL). Methods. An open-labeled, GH-controlled, multicenter study was conducted for 3 years. Non–GH-deficient short SGA children (n = 87), with a mean age (standard deviation) of 5.9 (1.5) years, were randomized to either a GH group (n = 61), receiving GH in a dose of 33 μg/kg/day, or an untreated control group (n = 26). Height; weight; HC; sitting height; armspan; and hand, tibial, and foot size were measured and expressed as standard deviation score (SDS) adjusting for gender and age. Results. At baseline, all anthropometric measurements, except HC SDS, were significantly lower compared with −2 SDS. During GH treatment, all anthropometric measurements normalized in accordance to the normalization of height SDS. At the start of the study, mean HC SDS was significantly lower in SGAL+W children compared with SGAL children. It is interesting that most (14 of 16) children with an HC SDS less than −2.00 had been born SGAL+W. During GH treatment, the 3-year increase in height, HC, and other anthropometric measurements was comparable between SGAL+W and SGAL children. In both SGAL+W and SGAL control subjects, no changes in SDSs of height, HC, and other anthropometric measurements were found during the 3-year follow-up period. Conclusions. Untreated short SGA children have normal body proportions with the exception of HC, which is relatively large in many of these children. SGAL+W children still had a smaller HC at the age of 5.9 years compared with SGAL children. Three years of GH treatment induced a proportionate growth resulting in a normalization of height and other anthropometric measurements, including HC, in contrast to untreated SGA control subjects.

Efficacy and safety of long-term continuous growth hormone treatment of children born small for gestational age.

Twelve years of growth hormone (GH) therapy of short children born small for gestational age (SGA) have demonstrated that GH is an effective and well-tolerated therapy. Most children will reach a normal adult height (AH). AH of 55 SGA adolescents was comparable for those treated with a GH dose of 1 or 2 mg/m2 (∼0.033 or 0.066 mg/kg) per day, mean (SD) AH SDS being –1.2 (0.7) and –0.8 (0.7), respectively. GH therapy had no influence on the age at onset, the progression of puberty, duration of puberty and pubertal height gain. GH therapy induced higher fasting and glucose-stimulated insulin levels after 1 and 6 years, but 6 months after GH stop, all levels returned to normal. At baseline mean systolic blood pressure was significantly increased, but both systolic and diastolic blood pressure decreased significantly during 6 years of GH and remained so after GH stop. GH therapy demonstrated a beneficial effect on serum lipid profiles, body composition, bone mineral density and head growth. Treatment with 2 mg GH/m2 per day induced mean serum IGF-I levels of +2 SDS, whereas IGF-I levels remained within the normal range with 1 mg GH/m2 per day. In conclusion, long-term GH therapy of short SGA children with 1 mg/m2 per day appears to be effective and safe. Since the future consequences of high serum IGF-I levels during long-term GH therapy with 2 mg/m2 per day are as yet unknown, it seems safer to treat short prepubertal SGA children with a GH dose of 1 mg/m2 per day when children are to be treated continuously for many years.

MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone‐deficient (GHD) children and children with normal stature

Background Disturbances in the GH/IGF‐I axis are reported in 25–60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls.

Birth Size, Postnatal Growth and Growth during Growth Hormone Treatment in Small-for-Gestational-Age Children: Associations with IGF1 Gene Polymorphisms and Haplotypes?

Background: Short small-for-gestational-age (SGA) children experience pre- and postnatal growth restriction, which might be influenced by polymorphisms in the IGF1 gene. The well-known –841(CA)n/192 bp polymorphism has been associated with birth size and cardiovascular disease. Aims: To determine whether birth size, postnatal growth and growth during growth hormone (GH) treatment, were associated with IGF1 gene polymorphisms and haplotypes. Methods: 201 short SGA children were investigated for four IGF1 gene polymorphisms in the promoter (–G1245A, –841(CA)n), intron 2 (+3703(CT)n) and 3UTR (+A1830G). Spontaneous growth and growth during GH treatment were studied. Results: The –1245 A allele was identified as a marker-allele for the well-known –841(CA)n/non-192 bp allele, both part of haplotype 2. The –1245 A allele was not associated with head circumference at birth, but was associated with a postnatal 0.3 SDS smaller head circumference at age 1–3. The –1245 A allele was also associated with a 1-week shorter gestational age which explained the association with a smaller absolute birth size. No associations were found with gestational age-adjusted birth size, height and weight SDS during postnatal life and with growth during GH treatment. Conclusions: The –G1245A SNP appeared to be a marker for the well-known –841(CA)n/192 bp polymorphism. Haplotype 2, of which the –1245 A allele was the marker, was associated with a smaller head circumference SDS during spontaneous postnatal growth, but not during GH treatment.

The -G1245A IGF1 polymorphism is related with small head size and less brain sparing in small for gestational age born children.

CONTEXT Small for gestational age (SGA) subjects experience pre- and postnatal growth restriction, which might be influenced by polymorphisms in the IGF1 gene. The well-known -841(CA)(n)/192 bp polymorphism has been associated with birth size, cardiovascular disease, and IGF-1 levels, and is in linkage disequilibrium with the -G1245A single nucleotide polymorphism (SNP; rs35767). OBJECTIVE To associate the -G1245A SNP with head circumference (HC) and brain sparing (a greater head compared with height SDS) in short SGA and SGA catch-up subjects. DESIGN Gene association study. PATIENTS We studied 635 SGA subjects out of which 439 remained short and 196 had a postnatal height >-2.00 SDS. MEASUREMENTS The -G1245A SNP IGF1 gene polymorphism and head size. RESULTS All SGA subjects had a postnatal head size below the population mean (-1.01 SDS, P<0.001). Whereas SGA catch-up subjects had a head size that was in proportion with their height, short SGA subjects displayed extensive brain sparing (HC - height: SGA CU: 0.01 versus short SGA: 1.75 SDS, P<0.001). The most severely SGA born subjects had a 0.4 SDS smaller postnatal head size and 0.6 SDS less brain sparing when carrying the -1245 A-allele in contrast to G-allele carriers (P=0.03). The association between the -G1245A SNP and head size remained significant after correction for birth weight and postnatal height SDS (P=0.03). Birth weight, birth length and postnatal height SDS were not related with the - G1245A SNP. CONCLUSIONS The -1245 A-allele of the IGF1 promoter SNP is associated with a small head size and less brain sparing in SGA born subjects and particularly those with the lowest birth weight.