Small For Gestational Age Boys Research Articles

Being born small for gestational age (SGA) might be associated with a higher reoperation rate in proximal hypospadias

Being born small for gestational age (SGA) is associated with a higher frequency and more severe forms of hypospadias as well as with potential developmental differences. This study aims to characterize operative outcomes in SGA boys compared to boys born with normal weight and length for gestational age (appropriate/large for gestational age, AGA/LGA). Demographic data, hypospadias characteristics, associated pathologies and operative outcomes of boys who underwent hypospadias repair at a single center (10/2012-10/2019) were evaluated. Boys were categorized into SGA and non-SGA, which were then compared using unpaired t-tests and chi square tests. To examine the effect of SGA on reoperative risk, a logistic regression model was applied integrating surgical technique, meatal localization and complex hypospadias (narrow glans/plate, curvature, micropenis, bilateral cryptorchidism). SGA boys accounted for 13.7% (n=80) of the total cohort (n=584) and 33% of all proximal hypospadias (n=99, SGA vs. non-SGA 41.3% vs. 13%, p<0.001). After a mean follow-up of 18.6 months the reoperation rate for all hypospadias was 17.9% (n=105). In distal hypospadias there was no difference in reoperation rate between SGA and AGA/LGA boys (p=0.548, multivariate regression model). For each meatal localization in proximal hypospadias SGA was a significant, independent factor predicting higher reoperation rates (p=0.019, OR 3.21) in a logistic regression model (Figure ROC). Hypospadias surgery carries a substantial risk for unplanned reinterventions. Apart from meatal localization, there are only a few factors (urethral plate quality, glandular diameter, curvature) reported in literature to be associated with reoperative risk. Intrauterine growth retardation associated with SGA might lead to not only a higher probability of proximal hypospadias but also contribute to a higher risk for complications mediated by developmental differences. Whether these findings could help to tailor surgical strategies or adjuvant measures, as for example the application of preoperative hormonal stimulation remains to be determined in future studies. This study is limited by being a single-center series with limited follow-up resulting in some complications probably not yet detected - however, in the same extent in both groups. Based on this study, 33% of all proximal hypospadias cases occur in boys born SGA. While the reoperation rate in boys with distal hypospadias was not influenced by SGA status, SGA proved to be an independent predictor of a higher risk of reoperation in those with proximal hypospadias. After validation of these findings in other centers, this could be integrated into counseling and risk-stratification.

Timing of Puberty, Pubertal Growth, and Adult Height in Short Children Born Small for Gestational Age Treated With Growth Hormone.

Growth hormone (GH) is used to treat short children born small for gestational age (SGA); however, the effects of treatment on pubertal timing and adult height are rarely studied. To evaluate adult height and peak height velocity in short GH-treated SGA children. Prospective longitudinal multicenter study. Participants were short children born SGA treated with GH therapy (n = 102). Adult height was reported in 47 children. A reference cohort of Danish children was used. Main outcome measures were adult height, peak height velocity, age at peak height, and pubertal onset. Pubertal onset was converted to SD score (SDS) using Danish reference data. Gain in height SDS from start of treatment until adult height was significant in both girls (0.94 [0.75; 1.53] SDS, P = .02) and boys (1.57 [1.13; 2.15] SDS, P < .001). No difference in adult height between GH dosage groups was observed. Peak height velocity was lower than a reference cohort for girls (6.5 [5.9; 7.6] cm/year vs 7.9 [7.4; 8.5] cm/year, P < .001) and boys (9.5 [8.4; 10.7] cm/year vs 10.1 [9.7; 10.7] cm/year, P = .002), but no difference in age at peak height velocity was seen. Puberty onset was earlier in SGA boys than a reference cohort (1.06 [-0.03; 1.96] SDS vs 0 SDS, P = .002) but not in girls (0.38 [-0.19; 1.05] SDS vs 0 SDS, P = .18). GH treatment improved adult height. Peak height velocity was reduced, but age at peak height velocity did not differ compared with the reference cohort. SGA boys had an earlier pubertal onset compared with the reference cohort.

Growth, puberty and testicular function in boys born small for gestational age with a nonspecific disorder of sex development.

Being born small for gestational age (SGA) is frequently associated with unexplained disorders of sex development (nonspecific DSD) in boys. Little is known about their future growth, puberty and testicular function. Our objective is to determine the long-term endocrine outcome of boys born SGA who have a nonspecific DSD. Boys with a nonspecific DSD born SGA and appropriate for GA (AGA) were retrieved through the International Disorders of Sex Development registry and retrospective data collected, based on a spreadsheet containing 102 items. In total, 179 boys were included, of which 115 were born SGA and 64 were born AGA. Their growth and pubertal development were compared. Serum LH, FSH, testosterone, AMH and inhibin B levels in infancy and puberty were analysed to assess testicular function. At 2 years of age, 30% of SGA boys had incomplete or absent catch-up growth. Boys born SGA also had higher LH during minipuberty and lower testosterone in stimulation tests (p = 0.037 and 0.040, respectively), as compared to boys born AGA. No differences were observed in timing or course of puberty or end-pubertal hormone levels. Almost one out of three SGA boys with a nonspecific DSD experiences insufficient catch-up growth. In addition, our data suggest dysfunction of infantile Leydig cells or altered regulation of the hypothalamic-pituitary-gonadal axis in SGA boys during childhood. Sex steroid production during puberty seems unaffected.

Maternal selenium deficiency during gestation is positively associated with the risks for LBW and SGA newborns in a Chinese population.

Maternal selenium (Se) deficiency is associated with some adverse pregnant outcomes. However, it remains controversial whether maternal Se deficiency during gestation enhances the risks for low-birth-weight (LBW) and small-for-gestational-age (SGA) newborns. For our cohort study, total 3133 mother-and-infant pairs were selected. Maternal serum Se concentration was detected by graphite furnace atomic absorption spectrometry. According to international references for maternal serum Se concentration, subjects were divided into Se deficiency (<45.0 μg/L), Se insufficiency (45.0-94.9 μg/L) and Se sufficiency (≥95.0 μg/L). There was a positive relation of maternal serum Se concentration in gestation and neonatal birth weight. Further analysis showed that the risks for LBW and SGA in SD group were significantly higher than that in SI and SS group, the adjusted ORs for LBW and SGA newborns were 1.87 (95%CI: 1.02, 3.45; P = 0.04) and 1.47 (95%CI: 1.07, 2.02; P = 0.02) in SI group, and 3.92 (95%CI: 2.03, 7.57; P < 0.001) and 2.77 (95%CI: 1.92, 4.02; P < 0.001) in SD group compared to SS group. In different gender subgroup, positive relations were observed between maternal Se deficiency and the risk for LBW girls, as well as the risks for both SGA girls and boys. Maternal Se deficiency in gestation was positively associated with the risk for LBW girls, as well as the risks for both SGA girls and boys.

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.

Being born small-for-gestational-age is associated with an unfavourable dietary intake in Danish adolescent girls: findings from the Danish National Birth Cohort.

Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) &lt;10th percentile (n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3-12%, P = 0.002) higher intake of added sugar and a 2-8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n-6, compared with NGA girls (P &lt; 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.

Brown adipose tissue in prepubertal children: associations with sex, birthweight, and metabolic profile.

Individuals born small-for-gestational age (SGA), especially those who experience postnatal catch-up growth, are at increased risk for developing endocrine-metabolic abnormalities before puberty. In adults, brown adipose tissue (BAT) has been associated with protection against metabolic disorders, such as obesity, type 2 diabetes, and dyslipidaemia. Here, we assessed for the first time whether BAT activation differs between prepubertal children born SGA or appropriate-for-gestational age (AGA). The study population consisted of 86 prepubertal children [41 AGA and 45 SGA; age (mean ± SEM), 8.5 ± 0.1 years], recruited into two prospective longitudinal studies assessing endocrine-metabolic status and body composition in infancy and childhood. The temperature at the supraclavicular region (SCR) before and after a cold stimulus was measured by infrared thermal imaging, and the area of thermally active SCR (increase after cold challenge, ΔAreaSCR) was calculated as a surrogate index of BAT activation. The results were correlated with clinical, endocrine-metabolic, and inflammation variables, and with visceral and hepatic adiposity (assessed by Magnetic Resonance Imaging). No differences in BAT activation index, as judged by ΔAreaSCR, were found between AGA and SGA children. However, girls showed higher baseline and post-cold induction AreaSCR than boys (both p ≤ 0.01). An interaction between gender and birth weight subgroup was observed for BAT activation; AGA girls increased significantly the ΔAreaSCR as compared to AGA boys; this increase did not occur in SGA girls vs SGA boys. Cold-induced ΔAreaSCR negatively correlated with HOMA-IR, us-CRP, liver volume, and liver fat. Prepubertal AGA girls had significantly greater BAT activation index as compared to AGA boys; this difference was not observed in SGA subjects. Higher BAT activation associated with a lower amount of visceral fat and with a favorable metabolic profile. Long-term follow-up is needed to determine whether those differences relate to pubertal timing, and to the development of obesity and metabolic disorders.

Overnight Levels of Luteinizing Hormone, Follicle-Stimulating Hormone and Growth Hormone before and during Gonadotropin-Releasing Hormone Analogue Treatment in Short Boys Born Small for Gestational Age

Aims: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone (GH) profiles and fasting insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels after 3 months of GnRHa treatment with those at baseline. Methods: After measurement of baseline overnight profiles and IGF-I and IGFBP-3 levels, 14 short pubertal SGA boys received leuprorelide acetate depots of 3.75 mg subcutaneously, every 4 weeks. Results: At baseline, mean GH levels were comparable with those of controls, whereas IGF-I and IGFBP-3 standard deviation scores (SDS) were significantly lower than zero SDS. After 3 months of GnRHa treatment, all boys showed clinical arrest of puberty. The area under the curve above zero, mean and maximum LH and FSH had significantly decreased to prepubertal levels. Peak LH during the GnRH agonist test, however, indicated insufficient pubertal suppression in 43% of boys. Overnight GH profile characteristics and IGF-I and IGFBP-3 levels did not significantly change. Conclusions: Puberty was sufficiently suppressed by GnRHa treatment, as shown by the prepubertal LH and FSH profiles. After 3 months of GnRHa treatment, overnight GH profile characteristics had not significantly changed, reflecting that GH levels are comparable for prepubertal and early pubertal boys.

Preterm birth or foetal growth impairment and psychiatric hospitalization in adolescence and early adulthood in a Swedish population‐based birth cohort

Preterm birth and restricted foetal growth are related to symptoms of psychiatric disorder. Our aim was therefore to investigate possible relations between being born preterm and/or small for gestational age (SGA) and later psychiatric hospitalization. A population-based registry study of psychiatric hospitalization of in total 155,994 boys and 148,281 girls born in Sweden in 1973-1975. The risk of hospitalization for all mental disorders was increased for preterm SGA boys (OR 2.19, 95% CI 1.49-3.21); at-term SGA boys (OR 1.55, 95% CI 1.34-1.79); at-term SGA girls (OR 1.31, 95% CI 1.15-1.50). At-term SGA boys and girls suffered increased risk of anxiety and adjustment disorders (OR 1.70, 95% CI 1.18-2.45 and OR 1.49, 95% CI 1.14-1.94). Preterm SGA boys were at risk of personality disorders (OR 3.30, 95% CI 1.16-9.41) and psychotic disorders (OR 4.36, 95% CI 1.85-10.30). The results show a relationship between being born SGA and later psychiatric hospitalization, where preterm birth and male gender seem to increase the risk.

Testis Function in Prepubertal Boys and Young Men Born Small for Gestational Age

Background/Aims: Some studies reported an impaired gonadal function in males born small for gestational age (SGA). We investigated Sertoli cell function by measuring serum inhibin B and antimullerian hormone (AMH) levels in prepubertal boys and young men born SGA in comparison with age-matched controls born appropriate for gestational age (AGA). Methods: Inhibin B and AMH levels were determined in 73 prepubertal short SGA boys and in 72 age-matched AGA boys. In addition, 25 SGA boys were re-examined after 2 years of growth hormone (GH) treatment. Furthermore, inhibin B, AMH, testosterone, LH and FSH were studied in three groups of young men: 21 SGA men treated with GH, 15 SGA men with spontaneous catch-up growth and 25 young men born AGA. Results: Prepubertal short SGA boys and AGA boys had similar inhibin B (87.3 and 78.2 ng/ml) and AMH levels (75.6 and 63.6 µg/l, respectively). GH treatment did not result in different inhibin B and AMH levels. In young SGA men, inhibin B, testosterone, LH and FSH levels were similar compared to young AGA men. AMH levels were higher in the young SGA men (p = 0.03). Conclusions: Being born SGA does not impair Sertoli cell function. Young men born SGA have a normal hypothalamic-pituitary-testis axis.

Circulating renin–angiotensin system and catecholamines in childhood: is there a role for birthweight?

There have been only a few reports on the sympathoadrenal and renin-angiotensin systems in children of small gestational age. The purpose of the present study was to investigate plasma levels of ACE (angiotensin-converting enzyme) activity, angiotensin and catecholamines in 8- to 13-year-old children and to determine whether there are correlations between the components of these systems with both birthweight and BP (blood pressure) levels. This clinical study included 66 children (35 boys and 31 girls) in two groups: those born at term with an appropriate birthweight [AGA (appropriate-for-gestational age) group, n=31] and those born at term but with a small birthweight for gestational age [SGA (small-for-gestational age) group, n=35]. Concentrations of angiotensin, catecholamines and ACE activity were determined in plasma. Circulating noradrenaline levels were significantly elevated in SGA girls compared with AGA girls (P=0.036). In addition, angiotensin II and ACE activity were higher in SGA boys (P=0.024 and P=0.050 respectively). There was a significant association of the circulating levels of both angiotensin II and ACE activity with BP levels in our study population. Although the underlying mechanisms that link restricted fetal growth with later cardiovascular events are not fully understood, the findings in the present study support the link between low birthweight and overactivity of both sympathoadrenal and renin-angiotensin systems into later childhood.

Pubertal Development in Children Born Small for Gestational Age

Reduced fetal growth appears to be associated with precocious adrenarche, early puberty and polycystic ovary syndrome with subsequent fertility problems. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) and children born appropriate for gestational age (AGA). Physical examination was carried out twice. Mean age (+/-SD) at the first visit: SGA group, 9.1+/-1.1 yr; AGA group, 9.0+/-1.1 yr. AT FOLLOW-UP: SGA group, 11.6+/-1.0 yr; AGA group, 11.6 +/-1.1 yr. Pubertal stages of the children were assessed. Pubic hair was recorded as a measure of androgenization. Chronological age (CA) was expressed as a percentage of the age corresponding to the pubertal stage (CA/pubertal age [PA] x 100%). Estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) were measured in all children. FIRST VISIT: All children were prepubertal without signs of pubarche. DHEAS concentrations were higher in SGA children than in AGA children (p = 0.004). Twenty SGA children and 15 AGA children were pubertal. CA/PA x 100% was lower in SGA girls than in AGA girls (p = 0.004). Since 2.5 years earlier all girls had been prepubertal, this means a more rapid progression in the SGA girls. CA/PA x 100% was similar in SGA and AGA boys (p = 0.1). DHEAS levels tended to be higher in SGA children than in AGA children (p = 0.06). These data support that a low birth weight may have long-lasting effects on pubertal development, as observed in a more rapid progression in SGA girls. In prepubertal SGA children, an exaggerated adrenarche is observed compared to AGA children, which tended to persist through puberty.

Hypersecretion of FSH in infant boys and girls born small for gestational age.

Prenatal growth restraint, as reflected in a low birthweight for gestational age, is a risk factor for postpubertal FSH hypersecretion and for reduced gonadal size. The ontogeny of the low-birthweight effect on the FSH-inhibin B feedback loop is unknown. Infancy is an episode of choice to study the possibility of an early low-birthweight effect on the FSH-inhibin B loop because this phase is characterized by high activity within the gonadal axis. We assessed serum concentrations of FSH and inhibin B in 46 infants [26 girls and 20 boys; mean age, 4 months; range, 3-6 months; 17 appropriate for gestational age (AGA), 29 small for gestational age (SGA); mean birthweight, 3.2 kg for AGA vs. 2.3 kg for SGA], together with circulating levels of LH, E2, and free androgen index. In SGA girls and boys, serum FSH levels were 2- and 4-fold higher (P < 0.001), respectively, than in AGA controls of the same gender (7.3 +/- 0.9 vs. 3.8 +/- 0.4 IU/ml and 2.9 +/- 0.5 vs. 0.7 +/- 0.2 IU/ml). Serum LH, inhibin B, and free androgen index/E2 concentrations were similar in AGA and SGA infants. In conclusion, prenatal growth restraint was found to be followed by elevated serum FSH concentrations in infant girls and boys. SGA infants seem to need an augmented FSH drive to fulfill inhibin B requirements on the afferent side of the feedback loop. The late-endocrine correlates of early growth restraint are herewith extended to include the main axis of reproduction in both genders. It remains to be studied whether FSH hypersecretion in infancy is a marker of subsequent subfertility.

Birthweight and stature, body mass index and fat distribution of 14-year-old Polish adolescents.

The relationships between intra-uterine growth retardation and stature, relative weight and fat distribution at adolescence have not been comprehensively established. The aim of this report is to assess the effect of low birthweight on stature, relative weight and fat distribution in 14-year-old boys and girls from Wroclaw, Poland. Cross-sectional measurements of 1197 boys and 819 post-menarcheal girls aged 13.50-14.49 years were performed during medical examinations in 1997. Stature, body mass index (BMI; kg/m2), waist-to-hip ratio (WHR) and waist-to-thigh ratio (WTR) were used in the present study. A cut-off value of the 10th percentile of birthweight for particular gestational weeks was used in order to define subjects born small for gestational age (SGA) or appropriate for gestational age (AGA). Two-way ANOVA was used to evaluate the effect of birthweight on anthropometric variables of 14-year-old adolescents, allowing for socioeconomic status (determined by the level of the mother's education). Birthweight affected stature in boys and girls (P < 0.001), BMI in boys (P < 0.05) and WHR and WTR in girls (P < 0.001 and P < 0.05, respectively). At the age of 14 years, both SGA boys and girls were shorter than their AGA peers. The SGA boys had lower BMI, whereas SGA girls accumulated more centralized fat compared with their AGA counterparts. Fetal growth retardation has a long-lasting adverse effect on later physical growth. Polish SGA children do not catch up with their peers in terms of stature by adolescence. Moreover, central fat distribution, as observed among SGA girls, constitutes a significant risk for several adult degenerative diseases.