Small For Gestational Age Individuals Research Articles

Thrifty-Eating Behavior Phenotype at the Food Court - Programming Goes Beyond Food Preferences.

IntroductionPrenatal growth impairment leads to higher preference for palatable foods in comparison to normal prenatal growth subjects, which can contribute to increased body fat mass and a higher risk for developing chronic diseases in small-for-gestational-age (SGA) individuals throughout life. This study aimed to investigate the effect of SGA on feeding behavior in children and adolescents, as well as resting-state connectivity between areas related to reward, self-control, and value determination, such as orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), amygdala and dorsal striatum (DS).MethodsCaregivers and their offspring were recruited from two independent cohorts in Brazil (PROTAIA) and Canada (MAVAN). Both cohorts included anthropometric measurements, food choice tasks, and resting-state functional magnetic resonance imaging (fMRI) data.ResultsIn the Brazilian sample (17 ± 0.28 years, n=70), 21.4% of adolescents were classified as SGA. They exhibited lower monetary-related expenditure to buy a snack compared to controls in the food choice test. Decreased functional connectivity (n=40) between left OFC and left DL-PFC; and between right OFC and: left amygdala, right DS, and left DS were observed in the Brazilian SGA participants. Canadian SGA participants (14.9%) had non-significant differences in comparison with controls in a food choice task at 4 years old ( ± 0.01, n=315). At a follow-up brain scan visit (10.21 ± 0.140 years, n=49), SGA participants (28.6%) exhibited higher connectivity between the left OFC and left DL-PFC, also higher connectivity between the left OFC and right DL-PFC. We did not observe significant anthropometric neither nutrients’ intake differences between groups in both samples.ConclusionsResting-state fMRI results showed that SGA individuals had altered connectivity between areas involved in encoding the subjective value for available goods and decision-making in both samples, which can pose them in disadvantage when facing food options daily. Over the years, the cumulative exposure to particular food cues together with the altered behavior towards food, such as food purchasing, as seen in the adolescent cohort, can play a role in the long-term risk for developing chronic non-communicable diseases.

Diminished insulin sensitivity is associated with altered brain activation to food cues and with risk for obesity – Implications for individuals born small for gestational age

While classically linked to memory, the hippocampus is also a feeding behavior modulator due to its multiple interconnected pathways with other brain regions and expression of receptors for metabolic hormones. Here we tested whether variations in insulin sensitivity would be correlated with differential brain activation following exposure to palatable food cues, as well as with variations in implicit food memory in a cohort of healthy adolescents, some of whom were born small for gestational age (SGA). Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was positively correlated with activation in the cuneus, and negatively correlated with activation in the middle frontal lobe, superior frontal gyrus and precuneus when presented with palatable food images versus non-food images in healthy adolescents. Additionally, HOMA-IR and insulinemia were higher in participants with impaired food memory. SGA individuals had higher snack caloric density and greater chance for impaired food memory. There was also an interaction between the HOMA-IR and birth weight ratio influencing external eating behavior. We suggest that diminished insulin sensitivity correlates with activation in visual attention areas and inactivation in inhibitory control areas in healthy adolescents. Insulin resistance also associated with less consistency in implicit memory for a consumed meal, which may suggest lower ability to establish a dietary pattern, and can contribute to obesity. Differences in feeding behavior in SGA individuals were associated with insulin sensitivity and hippocampal alterations, suggesting that cognition and hormonal regulation are important components involved in their food intake modifications throughout life.

OP03.04: Being born small for gestational age increases susceptibility to severe COVID‐19 in adulthood

Small for gestational age (SGA) may have long-lasting consequences with increased susceptibility to adult disease. We hypothesised that adults born SGA are more susceptible to develop severe COVID-19. An observational prospective study including 397 patients between 20 to 70 years old with confirmed COVID-19 infection attended in a tertiary hospital in Barcelona between March and May 2020. Epidemiological and perinatal variables were obtained from all patients by telephone interviews and hospital registers. Patients were divided according to their birthweight: born small-for-gestational age (SGA, n = 65) defined by birthweight below the 10th centile versus non-SGA (n = 332). Baseline and clinical COVID-19 characteristics were compared among groups. Baseline variables including gender, body mass index, smoking status and previous comorbidities were similar among groups. Adult COVID-19 patients who were born SGA presented higher rates of severe disease and need for admission to Intensive Care Unit (23.1% vs 13.6%, p = 0.043) as compared to non-SGA individuals. SGA individuals had also a non-significant trend of pneumonia rates (80% vs 71%, p = 0.083). Being born SGA seems to increase susceptibility to severe COVID-19 infection in non-elderly adults, reinforcing the importance of early life in the predisposition to adult disease.

OP06.03: Cardiac magnetic resonance in young adults born small for gestational age reveals right ventricular remodelling

Cardiac remodelling and dysfunction occur in small-for-gestational age (SGA) fetuses and children, but it is uncertain whether and how these effects persist into adulthood. We aimed to evaluate cardiac structure and function in SGA young adults. A perinatal cohort from a tertiary university hospital in Spain, including young adults (30-40y) born SGA (birth weight below 10th centile, n = 61) and with normal intrauterine growth (n = 66). Cardiac structure and function were assessed by cardiac magnetic resonance including biventricular end-diastolic shape analysis. Results were adjusted by age, gender, asthma, education, smoking habit, gestational age at delivery, breastfeeding and gestational hypertension. SGA individuals showed similar indexed cardiac dimensions, mass, relative wall thickness and function. Shape analysis demonstrated significant changes in right ventricular geometry with slight flattening of the basal septum and wider RV base in SGA compared to controls (Delong test p = 0.02, figure 1). Young adults born SGA showed significant changes in right ventricular geometry. These results support further research to clarify the potential links with increased cardiovascular mortality in adults born SGA. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

SUN-246 Low Frequency of Pathogenic Allelic Variants in the Disorders of Sex Development Related Genes in Small for Gestational Age Children with Hypospadias

Background: Small for gestational age (SGA) children are defined as the one with birth weight and/or length 2 or more standard deviations below the population mean for gestational age. The underlying causes of pre and postnatal growth failure are diverse1. SGA boys present a high frequency of hypospadias (15 to 30%) of unknown etiology2. Objective: To analyze the prevalence of SGA individuals with hypospadias in a large cohort of 46, XY disorders of sex development (DSD) patients (n=272) followed in a tertiary center and to search for a molecular etiology associated with this phenotype. Patients and methods: We evaluated 30 SGA children with medium or proximal hypospadias, four of them presented syndromic characteristics associated. DNA samples of 24 patients were studied by target massively parallel sequencing (TPMS) using an amplicon-based capture panel of 63 genes related to DSD, and one by whole exome sequencing (WES). TPMS and WES were performed in the Illumina MiSEQ/HiSEQ platforms, respectively. Paired-end reads were aligned to the hg19 assembly of the human genome with BWA-MEM. Variants were called and annotated with Platypus and ANNOVAR. Results: The prevalence of SGA individuals with hypospadias in the 46, XY DSD cohort was 11%. Two children had clinical features of Silver-Russell syndrome and their diagnosis was confirmed (11p15 LOM) by MLPA. The two other syndromic patients were suspected with three M syndrome and Mulibrey Nanism. The TPMS study identified three likely pathogenic variants in these patients: p.Trp1538* and p.Gln813fs variants in compound heterozygosis in CUL7 gene and the homozygous p.Gly340fs variant in TRIM37. Seven heterozygous variants with uncertain significance in 5 DSD related genes were identified: two in the DHX37, p.V717I and p.A737T, associated with GATA4 p.P407R variant and with WWOX p.Y85D, respectively; the WT1 p.C350R variant, the IGF1R p.R1337C variant, and the BMP8B p. Arg116Cys variant. The frequency of likely pathogenic variants in SGA children with hypospadias was 10%. Conclusion: The low frequency of pathogenic allelic variants identified in SGA children with hypospadias indicates that other mechanisms, as epigenetic changes, may be involved in the etiology of this condition. 1 CLAYTON, P. E. et al. Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. The Journal Of Clinical Endocrinology & Metabolism, [s.l.], v. 92, n. 3, p.804-810, mar. 2007. The Endocrine Society. http://dx.doi.org/10.1210/jc.2006-2017. 2 MOREL, Y et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. European Journal Pediatric, [s. L.], v. 161, n. 1, p.49-59, jan. 2002.

Early Growth Hormone Intervention Improves Glucose Metabolism in Adult Rats Born Small for Gestational Age.

Small for gestational age (SGA) due to intrauterine malnourishment is closely related to metabolic syndrome and type 2 diabetes mellitus. Growth Hormone (GH) treatment has been demonstrated to influence metabolic parameters and islet function of SGA individuals. The present study demonstrates the effects of early GH treatment on glucose tolerance and expression of pancreatic duodenal homeobox 1 (Pdx1) of SGA rats during adulthood. SGA rat model was induced by restricting food intake during pregnancy. GH or normal saline was administered during postnatal days 21-35 of SGA rats and appropriate for gestational age (AGA) rats, respectively. In early adulthood (postnatal day 70), as compared to AGA rats, SGA rats showed: (1) decreased body weight; (2) increased postprandial blood glucose; and (3) down-regulated Pdx1 with increased histone deacetylase (HDAC) and down-regulated histone H3-lysine 4 methyltransferase SET7/9. Exogenous GH administration led to a restoration of body weight and normalized glucose tolerance due to an enhanced Pdx1 expression, accompanied by decreased HDAC and up-regulated SET7/9 in SGA rats in early adulthood. Our results demonstrate positive effects on glucose metabolism by an early and short GH treatment in SGA adulthood.

The Impact of Being Born Preterm or Small for Gestational Age on Early Vascular Aging in Adolescents

To assess the impact of being born preterm or small for gestational age (SGA) on early vascular aging (EVA) in a cohort of healthy Tyrolean adolescents. This study is part of an ongoing clinical trial, EVA Tyrol, a regional cohort study being conducted in western Austria. EVA was assessed in adolescents (mean age, 16 years) by means of carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (cIMT), and blood pressure measurements. Adolescents were grouped as either term or preterm. Subsequently, being born SGA was taken into consideration in subgroup analysis. Complete data on gestational age and birth weight were available for 930 adolescents. Systolic blood pressure and diastolic blood pressure were significantly higher in the preterm (mean gestational age, 34.8 ± 2.3 weeks) and appropriate for gestational age (AGA) group than in the term and AGA group (P < .05). This finding remained significant in linear regression analysis after adjustment for covariables in all models. PWV was significantly higher in the term-SGA group than in the term-AGA group (6.67 ± 1.73 m/s vs 6.07 ± 1.09 m/s; P < .05). In the linear regression analysis, this finding remained significant in all models. There were no differences in cIMT between study groups. Being born preterm or SGA might render persons susceptible to EVA. Long-term follow-up of preterm and SGA individuals is warranted to confirm these results.

Role of Peroxisome Proliferator-Activated Receptor (PPARγ) in Metabolic Disorders in SGA with Catch-Up Growth.

Abnormal fat metabolism is a major disorder in adults who were small for gestational age (SGA). Peroxisome prolferator-activated receptor (PPARγ) participates in adipocyte differentiation and the regulation of lipid metabolism. This study explored the role of PPARγ in the regulation of fat catch-up growth (CUG) and the lipid metabolism of SGA individuals. The CUG-SGA rats were treated with pioglitazone. The weight of the visceral adipose tissue, serum lipid levels, and PPARγ expression in the visceral adipose tissue were detected at 4, 8, and 12 weeks of age. The PPARγ expression in the visceral adipose tissue in the CUG-SGA group was lower than that in the appropriate for gestational age (AGA) group at 4, 8, and 12 weeks (P < 0.05). The serum triglycerides in the CUG-SGA group were elevated compared with that in the AGA group at 4 and 12 weeks (P = 0.005; P = 0.037); however, they were significantly decreased after 8 weeks of pioglitazone intervention (P = 0.001). PPARγ expression in the visceral adipose tissue was lower in SGA rats and may be related to the regulation of adipocyte differentiation. The early increased PPARγ expression by pioglitazone might reduce serum triglycerides and decrease the CUG of the visceral adipose tissue in SGA.

Dopamine transporter (DAT1/SLC6A3) polymorphism and the association between being born small for gestational age and symptoms of ADHD

Being small for gestational age (SGA) has been established as a risk factor for Attention Deficit Hyperactivity Disorder (ADHD). Likewise, several molecular genetic studies have found a link between DAT1 and ADHD. This study investigated whether SGA moderates the effect of dopamine transporter gene variants on the risk of ADHD. A total of 546 children of European descent were genotyped at age 11 for seven DAT1 SNPs (rs6347, rs11564774, rs40184, rs1042098, rs2702, rs8179029 and rs3863145). The Strengths and Difficulties Questionnaire was used to measure symptoms of ADHD at ages 3.5, 7 and 11. We found significant gene-environment interactions between birth weight and DAT1 SNPs (rs6347, rs40184, rs1042098, rs3863145) on ADHD symptoms at 3.5 years only. Results suggest that genotypic variation of DAT1 may confer a relative protective effect against ADHD in SGA individuals. This study supports the idea that being born SGA moderates the effect of the DAT1 gene on ADHD symptoms in the preschool years and may help to explain some of the heterogeneity in ADHD outcomes.

Preterm Children Born Small for Gestational Age are at Risk for Low Adult Bone Mass.

Cross-sectional studies suggest that premature birth and low birth weight may both be associated with low peak bone mass. We followed bone traits in preterm individuals and controls for 27 years and examined the effects of birth weight relative to gestational age [stratified as small for gestational age (SGA) or appropriate for gestational (AGA)] on adult bone mineral density (BMD). We measured distal forearm BMC (g/cm) and BMD (g/cm(2)) with single-photon absorptiometry (SPA) in 46 preterm children (31 AGA and 15 SGA) at mean age 10.1 years (range 4-16) and in 84 healthy age-matched children. The measurements were repeated 27 years later with the same SPA apparatus but then also with dual energy absorptiometry and peripheral computed tomography (pQCT). Preterm individuals were shorter (p = 0.03) in adulthood than controls. Preterm AGA individuals had similar BMC and BMD height-adjusted Z-scores in adulthood compared to controls. Preterm SGA individuals had lower distal forearm BMC and BMD height-adjusted Z-scores in adulthood than both controls and preterm AGA individuals. Preterm SGA individuals had lower gain from childhood to adulthood in distal forearm BMC height-adjusted Z-scores than controls (p = 0.03). The deficits in preterm SGA individuals in adulthood were also captured by DEXA in height-adjusted femoral neck (FN) BMC Z-score and height-adjusted FN BMD Z-score and by pQCT in tibial cross-sectional area (CSA) Z-score and stress strain index (SSI) Z-score, where all measurements were lower than controls (all p values <0.05). Preterm SGA individuals are at increased risk of reaching low adult bone mass, at least partly due to a deficit in the accrual of bone mineral during growth. In our cohort, we were unable to find a similar risk in preterm AGA individuals.

ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content.

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.

Perinatal growth restriction is not related to higher intestinal distribution and increased serum levels of 5-hydroxytryptamin in piglets1

Serotonin [5-hydroxytryptamin (5-HT)] is abundantly present in intestinal enteroendocrine cells and neurons and plays a crucial role in gastrointestinal functions (i.e., motility and mucosal secretion). Increased concentrations of 5-HT and its precursor l-Trp are present in plasma and brain tissues in case of intrauterine growth retardation (IUGR). Therefore, 5-HT might be involved in the impaired gastrointestinal function associated with IUGR. Small-for-gestational-age (SGA) piglets have been widely used as animal model for IUGR. Hence, the density of intestinal 5-HT cells in fetal and neonatal SGA piglets was compared with serotonergic cell density in normal weight (NW) littermates. Furthermore, 5-HT serum concentrations of the neonatal piglets were analyzed. Stereological analysis showed that fetal piglets have higher (P < 0.01) volume densities of 5-HT enteroendocrine cells compared to 3-d-old piglets irrespective of BW. Serum concentrations did not differ in relation to postnatal age (P = 0.637) and BW (P = 0.892). These results contrast with serum and brain 5-HT and l-Trp levels in human and guinea pig SGA individuals and seemingly contest the fact that 5-HT plays an important role in gut impairment in SGA.

Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder

The term small for gestational age (SGA) refers to infants whose birth weights and/or lengths are at least two standard deviation (SD) units less than the mean for gestational age. This condition affects approximately 3%–10% of newborns. Causes for SGA birth include environmental factors, placental factors such as abnormal uteroplacental blood flow, and inherited genetic mutations. In the past two decades, an enhanced understanding of genetics has identified several potential causes for SGA. These include mutations that affect the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, including mutations in the IGF-1 gene and acid-labile subunit (ALS) deficiency. In addition, select polymorphisms observed in patients with SGA include those involved in genes associated with obesity, type 2 diabetes, hypertension, ischemic heart disease and deletion of exon 3 growth hormone receptor (d3-GHR) polymorphism. Uniparental disomy (UPD) and imprinting effects may also underlie some of the phenotypes observed in SGA individuals. The variety of genetic mutations associated with SGA births helps explain the diversity of phenotype characteristics, such as impaired motor or mental development, present in individuals with this disorder. Predicting the effectiveness of recombinant human GH (hGH) therapy for each type of mutation remains challenging. Factors affecting response to hGH therapy include the dose and method of hGH administration as well as the age of initiation of hGH therapy. This article reviews the results of these studies and summarizes the success of hGH therapy in treating this difficult and genetically heterogenous disorder.

DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; “AGA”). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10-13) and head circumference at birth (P=4.1x10-13). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.

Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age

Insulin resistance (IR) and the metabolic syndrome (MS) have been reported in adults as a consequence of being born small for gestational age (SGA). The process seems to be initiated early in life; however, little is known about the progression of MS and IR in young adults. We hypothesised that being born SGA would promote a greater progression over time of IR and MS, reflecting not only the gain in weight and fat mass but also the extension of the fetal programming process. Participants were selected from a community-based cohort and born full-term either SGA (birthweight <10th percentile) or appropriate for gestational age (25th < birthweight < 75th percentile). A total of 1,308 individuals were prospectively followed between the ages of 22 and 30 years. At both ages, individuals born SGA were more insulin-resistant and showed a significantly higher prevalence of MS. Over the 8 year follow-up, the risk of developing MS was twofold higher in those SGA, after adjustment for gain in BMI, whereas the progression of IR was not significantly affected by the birth status. Our data suggest that metabolic disorders in SGA individuals are amplified by the weight gain with time when adults, both probably resulting from fetal programming. Moreover, the modest increase in IR contrasts with the constant and much higher prevalence of MS.

Consequences of Being Born Small for Gestational Age on Body Composition: An 8-Year Follow-Up Study

Increased fat mass has been reported in children and adults born small for gestational age (SGA). However, the progression of anthropometric parameters have been poorly documented in SGA adults. We hypothesized that SGA individuals would remain susceptible to gain more fat when adults beyond the period of postnatal catch-up growth. From a community-based cohort, 389 subjects born full-term SGA (body weight < 10th percentile) were compared with 462 subjects born appropriate for gestational age (25th < body weight < 75th percentile). Anthropometric parameters were measured at 22 and 30 yr as well as body composition (by multifrequency bioelectrical impedancometry and skinfold thickness) at 30 yr. Both groups gained weight, body mass index (BMI), and waist circumference. Progression of BMI was significantly greater in SGA (1.8 +/- 2.6 vs. 1.4 +/- 2.6 kg/m(2); P = 0.03). At 30 yr, the proportion of obese individuals was significantly increased in SGA (12.1 vs. 6.5%; P = 0.02), and percent body fat was significantly higher (23.5 +/- 8.7 vs. 21.9 +/- 8.0%; P = 0.01), the observation of which was confirmed by skinfold measures. Similarly, waist circumference gain was significantly greater in SGA (6.4 +/- 7.6 vs. 5.5 +/- 7.9, P = 0.04 when adjusted for gender and age). Over 8-yr follow-up, adults born SGA gained more BMI than appropriate for gestational age, resulting in greater fat mass with more abdominal fat. These data suggest that the consequences of fetal growth restriction on body composition are evolving beyond the period of early postnatal catch-up.

Final Height in Short Children Born Small for Gestational Age Treated with Growth Hormone

The aim of this observational study was to assess the long-term growth responses to GH treatment of children born small for gestational age (SGA). GH treatment was begun before puberty and continued to final height (FH). Seventy-seven short (height SD score below -2) prepubertal children born SGA (below -2 SD for birth weight and/or birth length), with a broad range of GH secretory capacity, were treated with GH in a daily dose of 33 microg/kg (0.1 U/kg), beginning before the onset of puberty. We observed a difference between adult and pretreatment projected height of 1.3 SD (9 cm) for the entire group. Among the children treated for >2 y before puberty, this mean gain (i.e. difference) in final height was 1.7 SD, whereas the mean gain was 0.9 SD among those in whom treatment was begun <2 y before puberty. Better catch-up growth was observed in the younger (r=-0.56, p<0.0001), shorter (r=-0.49, p<0.0001), and lighter (r=-0.46, p<0.0001) subjects. We conclude that GH treatment improves the final height of short children born SGA. The height gain attained before the onset of puberty is maintained to final height. The younger, shorter, and lighter the child at the start of GH treatment, the better the response. Moreover, most of these SGA individuals treated with GH reach their target height.