Leptin levels at birth and in early postnatal life in small- and appropriate-for-gestational-age infants.

UNLABELLED: The aim of this study was to evaluate leptin concentration at birth and in early postnatal life in small- and appropriate-for-gestational-age infants and to assess its relationship with infants' anthropometry at birth and some characteristics of maternal pregnancy. MATERIALS AND METHODS: A total of 367 infants born after 32-42 weeks of gestation were enrolled in the study. Umbilical cord blood samples were collected from 80 small- and 287 appropriate-for-gestational-age newborns. Altogether, 166 venous blood samples were taken from these neonates on days 2-6 of life. RESULTS: Cord leptin levels were significantly lower in small- compared to appropriate-for-gestational-age infants. We observed a positive correlation between cord leptin and birth weight, all neonatal anthropometric parameters, placental weight, and some maternal nutritional factors. In multivariate analysis, cord leptin concentration explained up to 15% of the variation in sum of newborn's skinfold thickness but only 5% of the variation in birth weight. Postnatally, leptin concentration decreased markedly to the similar low levels in both infant groups and remained so during the first postnatal week. CONCLUSIONS: Significantly lower cord leptin concentration in small-for-gestational-age neonates reflects a lower fat mass content compared to appropriate-for-gestational-age infants. However, an abrupt decrease in leptin levels shortly after birth in both groups suggests that placenta could be an important source of leptin in fetal circulation. The impact of low leptin levels at birth in small-for-gestational-age infants on their postnatal appetite and weight gain remains to be elucidated in future studies.

Reference values for insulin-like growth factor-binding protein-3 (IGFBP-3) and the ratio of insulin-like growth factor-I to IGFBP-3 throughout childhood and adolescence.

To facilitate the diagnosis of GH deficiency and monitor GH therapy, we constructed two reference models to allow comparison of serum IGF binding protein (IGFBP)-3 concentrations and IGF-I to IGFBP-3 ratios among children throughout childhood and adolescence. This report presents equations for determining the sd score of IGFBP-3 and IGF-I to IGFBP-3 measurements for individual patients. The data set contains serum values from 468 healthy children and adolescents (232 males, 236 females; ages 1.1-18.3 yr) whose height, weight, and body mass index were within +/- 3 sd of means. Puberty was classified according to breast development (B) and testicular volume into pre-, early, mid-, and late puberty. The values of IGFBP-3 and IGF-I to IGFBP-3 ratios were log transformed, and multiple linear regression analysis was used to identify models for converting serum concentrations into sd scores. The models include the variables of age, gender, and puberty and take into account the interactions among these variables. The best linear models explain 42% of the variation in serum IGFBP-3 concentrations and 50% of the variation in serum IGF-I to IGFBP-3 concentrations. The relationship between age and log(IGFBP-3) was positive for boys in pre-, early, and midpuberty. In late puberty, values were higher than earlier in puberty, and there was a negative relationship with age. For girls the relationship between age and log(IGFBP-3) also was positive in pre- and early puberty, with larger effect for girls older than 8 yr. Values for girls in midpuberty were relatively constant, and in late puberty values were higher than earlier in puberty, and there was a negative relationship with age. The relationship between age and log(IGF-I to IGFBP-3 ratio) was positive for boys in pre-, early, and early midpuberty (volume = 9-14 ml). In late midpuberty (volume = 15-19 ml), the relationship between age and IGF-I to IGFBP-3 ratio was negative. In late puberty, values were relatively constant and higher than earlier in puberty. For girls in prepuberty, the relationship with age was positive, with a larger effect in girls older than 8 yr. In early puberty, the girls' values were relatively constant. In early midpuberty (B = 3), log(IGF-I to IGFBP-3 ratio) values were higher for girls than boys of the same age. In late midpuberty (B = 4), the relationship with age was negative, and in late puberty values were relatively constant and higher than earlier in puberty.

Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database).

A model was developed that allows physicians to individualize GH treatment in children born short for gestational age (SGA) who fail to show spontaneous catch-up growth. Data from children (n = 613) in a large pharmacoepidemiological survey, the KIGS (Pharmacia International Growth Database), or who had participated in clinical trials were used to develop the model. Another group of similar children (n = 68) from KIGS was used for validation. In the first year of GH treatment, the growth response correlated positively with GH dose, weight at the start of GH treatment, and midparental height SD score and negatively with age at treatment start. Using this model, 52% of the variability of the growth response could be explained, with a mean error SD of 1.3 cm. GH dose was the most important response predictor (35% of variability), followed by age at treatment start. The second year growth response was best predicted by a three-parameter model (height velocity in yr 1 of treatment, age at start of treatment, and GH dose), which accounted for 34% of the variability, with an error SD of 1.1 cm. The first year response to GH treatment was the most important predictor of the second year response, accounting for 29% of the variability. No statistically significant differences between the predicted and observed growth responses were found when the models were applied to the validation groups. In conclusion, using simple variables, we have developed a model that can be used in clinical practice to adjust the GH dose to achieve the desired growth response in patients born SGA. Furthermore, this model can be used to provide patients with a realistic expectation of treatment and may help to identify compliance problems or other underlying causes of treatment failure.

Association between insulin-like growth factor I (IGF-I) polymorphisms, circulating IGF-I, and pre- and postnatal growth in two European small for gestational age populations.

The purpose of this study was to assess the association of IGF-I and birth size by studying small for gestational age (SGA) subphenotypes and undertaking more detailed analysis of IGF-I genetic markers. SGA subjects from Haguenau, France (n = 113), and Gothenburg, Sweden (n = 174), were studied. The Swedish subjects were subphenotyped according to postnatal growth (114 short SGA and 60 SGA catch-up). IGF-I dinucleotide repeat and single nucleotide polymorphism (SNP) markers were studied, and haplotypes were generated in the Swedish short SGA group by identity of state. Association analysis was undertaken using the Monte Carlo method of association analysis of multiallelic markers for dinucleotide repeat markers, by exact chi(2) analysis for SNPs and by ANOVA for serum IGF-I levels. IGF-I genotype was associated with the SGA phenotype, in particular with symmetrical SGA and low birth weight, and with IGF-I levels in SGA subjects. Association with postnatal growth was different in the two populations, which may reflect the power of the smaller subphenotype groups. Haplotype analysis in the Swedish short SGA subjects showed that the region of association lay between the promoter and intron 2 of the IGF-I gene. These studies validate the association of the IGF-I gene with birth size and refine the region of association in Swedish short SGA subjects.

Short boys treated with growth hormone show normal progression of testicular size and achieve normal serum testosterone concentrations.

OBJECTIVE: To determine whether there is evidence for impaired testicular function at final height in short boys treated with growth hormone (GH) during their childhood and adolescence. STUDY DESIGN: The analysis was restricted to males who had isolated GH deficiency or idiopathic short stature, and who were included in the Swedish National Registry and the Swedish GH trials. The subjects had to have been treated with GH for at least 4 years; the treatment had to have been started prepubertally, given for at least one year before the onset of puberty and the subjects had to have reached final height. One hundred and eleven boys fulfilled the criteria. METHODS: Testicular volumes were determined by orchidometer in each boy when GH treatment was started and at final height. Samples for testosterone measurements were collected from 77 boys at final height, and were measured by RIA. RESULTS: Each subject had normal testicular size (15 ml or more) and for those in whom concentrations were determined, serum testosterone levels and diurnal rhythm were normal. CONCLUSIONS: The results of our survey do not show evidence of testicular impairment following GH therapy.

Parents' experiences of receiving the diagnosis of Turner syndrome: an explorative and retrospective study.

Turner syndrome (TS) is a sex-chromosome disorder occurring in approximately 1:2500 female births. In this explorative and retrospective study, 44 parents (33 mothers and 11 fathers) from different families, each containing a girl with TS, were interviewed to explore their perceptions and experiences of the diagnostic process, including the period of investigation and the time when the diagnosis was given. There was wide variation in degree of retrospection in this study; one parent who was interviewed had a daughter of 17 years of age who was diagnosed before 1 month of age. On the other hand, two girls had been diagnosed only 6 months before their parents were interviewed. Most parents (n=27) reported that it was professionals who observed that their daughter should be referred for investigation, and the remainder (n=17) reported that they themselves perceived the need for investigation. Their experiences were found to affect the parents' descriptions of the diagnostic process. The parents who initiated the investigation themselves described the diagnosis in terms of confirmation of their own suspicions. When professionals initiated the investigation the parents reported that they felt unprepared when they received the diagnosis. The results of this study indicate that the parents' experiences of receiving the diagnosis of TS appear to depend on the ability of the doctor to provide relevant information and to manage the psychosocial aspects correctly. A better understanding of parents' experiences should enable health professionals to counsel parents more effectively concerning the diagnosis of TS.

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.

Improved final height with long-term growth hormone treatment in Noonan syndrome.

AIM: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height. METHODS: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria. GH treatment started at an age ranging from 3.1 to 13.8 y and was continued for at least 2 y. Improvement or "gain" in final height (FH) was defined as either the difference between adult height SD scores (SDS) and pre-treatment height SDS (the childhood component of the Swedish reference) or height SDS compared to the Noonan reference. RESULTS: Ten children received a GH dose of 33 microg/kg/d (mean age at start 7.7+/-2.1 y, mean age at stop 17.6+/-1.7 y) and 15 received a dose of 66 microg/kg/d (mean age at start 8.6+/-3.3 y, mean age at stop 18.4+/-2.1 y). Eighteen out of 25 patients reached FH. A substantial improvement in FH of 1.7 SDS, equivalent to 10.4 cm compared to pre-treatment height, was observed. No significant difference was seen between the two GH doses. Females gained a mean height of 9.8 cm and males 1-13 cm (FH 174.5+/-7.8 cm vs mean adult height of 162.5+/-5.4 cm for males with NS) at final height. Moreover, 60% reached a mid-parental height of+/-1 SD. CONCLUSION: GH treatment improves final height in patients with Noonan syndrome, with a mean gain of 1.7 SDS. The prepubertal height gain is maintained to final height and the children achieve a height close to their mid-parental height.

The role of maternal factors, postnatal nutrition, weight gain, and gender in regulation of serum IGF-I among preterm infants.

IGF-I is important for somatic growth and development of the human fetus and neonate. IGF-I also plays an important role in normal vascularization of human retina, as it has been suggested that insufficient IGF-I may be a factor in the development of retinopathy of prematurity. The principal regulator of the bioavailability of IGF-I in the circulation is IGF binding protein 3 (IGFBP-3). The aim of this study was to study factors associated with postnatal serum concentrations of IGF-I and of IGFBP-3 in preterm infants from birth to an age corresponding to 40 wk postmenstruation. We conducted a prospective, longitudinal study in which we measured serum IGF-I and IGFBP-3 concentrations in 76 preterm infants from birth (postmenstrual ages 23-32 wk) until discharge from hospital around 40 wk. Information regarding nutrition, weight gain, maternal factors, and treatment with corticosteroids were collected weekly. Variables found to be associated with postnatal change over time of serum IGF-I and IGFBP-3 were postmenstrual age (p<0.001), weight gain (standard deviation score) (p<0.001), and enteral intake of protein (p<0.001). Male gender was associated with lower IGF-I levels (p<0.001). The relationship between protein intake and IGF-I (and also between protein intake and IGFBP-3) was positive, as was the relationship between weight gain and IGF-I (and between weight gain and IGFBP-3). These results indicate that the degree of prematurity, low enteral protein intake, male gender, and slow weight gain are associated with a slower postnatal increase of IGF-I in preterm infants.

Growth prediction models, concept and use.

There is a principal and qualitative difference between using regression results on data from groups of children, and using validated prediction models for individual children. Using accurate models, it is now possible to predict the growth response to growth hormone (GH) treatment in a slowly growing child with GH deficiency (GHD) or in a child with idiopathic short stature (ISS). The growth response to the standard dose of GH can be regarded as a bioassay for GH (i.e. the tissue GH responsiveness) and the information on this growth response can be used for different purposes: to decide about treatment or not, for monitoring, and for adjusting the GH dose in order to reach a defined goal for height. This last concept is now used in an ongoing prospective randomized GH dose-finding trial.

Growth in very preterm children: a longitudinal study.

The knowledge about the long-term growth of very preterm children in relation to gestational age at birth is incomplete. Therefore, a retrospective study of longitudinal growth from birth to 7 y of age in 52 of 56 surviving children who were born at a gestational age of <29 wk between 1988 and 1991 to mothers resident in the city of Göteborg, Sweden, was performed. A majority of the children had an initial decrease in weight during the first months of life, followed by an increase, with a maximum weight gain occurring at 36-40 wk postmenstrual age. After a period of decreased weight and length velocity, a second increase in weight velocity was demonstrated from 6 mo to 2 y of corrected age. A corresponding increase in length velocity was found from 2 to 12 mo of corrected age. A later catch-up growth period was found at 4-5 y of age. At 7 y of age, all but two had reached the normal height range of the population. This long-term catch-up in height was established later in those who were born at an earlier gestational age. We conclude that all preterm infants had an initial period of poor growth, which rendered them growth retarded during the first years of life. It took approximately 4-7 y to overcome what the very preterm child lost in growth during the first months of life. However, as a group, they did reach normal height, weight, and weight for height before puberty.