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Abstract Background Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. Aim To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). Material and method In NESGAS, short SGA children (n = 101, 61 males) received GH at 67 µg/kg/day for 1 year. IGF-I concentrations were measured by Immulite immunoassay and bioactive IGF by in-house KIRA assay. Results Bioactive IGF increased with age in healthy pre-pubertal children (n = 94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, P < 0.01. Following high-dose GH, 68% (n = 65) of SGA children had a total IGF-I concentration >2SD (mean IGF-I 2.8 SDS), whereas only 15% (n = 15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r = 0.29, P = 0.005), in contrast to IGF-I (SDS) (r = 0.17, P = 0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r = -0.22, P = 0.02). Conclusion In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment.

Abstract Context Somapacitan, a once-weekly reversible albumin-binding growth hormone (GH) derivative, is evaluated in short children born small for gestational age (SGA). Objective Evaluate efficacy, safety, tolerability as well as total and bioactive insulin-like growth factor I (IGF-I) response of once-weekly somapacitan compared to daily GH in children born SGA. Methods REAL5 is a randomized, multicenter, open-label, controlled phase 2 study comprising a 26-week main phase, a 26-week extension, and an ongoing 4-year safety extension (NCT03878446), conducted at 38 sites across 12 countries. A total of 62 GH-treatment-naïve, prepubertal short children born SGA were randomized; 61 completed 52-weeks of treatment. Patients were randomized (1:1:1:1:1) to somapacitan (0.16, 0.20, or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day), all administered subcutaneously. Results Estimated mean height velocity (HV; cm/year) at week 52 was 8.5, 10.4, and 10.7 cm/year for somapacitan 0.16, 0.20, and 0.24 mg/kg/week, respectively, and 9.3 and 11.2 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Dose-dependent increases in total IGF-I, as well as peak IGF-I bioactivity, were observed for both treatments and were similar between comparator groups. For somapacitan, exposure-response modeling indicated highest efficacy with 0.24 mg/kg/week after 52 weeks of treatment. Similar safety and tolerability were demonstrated across all groups. Conclusion A sustained dose-dependent growth response was demonstrated for somapacitan after 52 weeks of treatment. Overall, somapacitan 0.24 mg/kg/week provides similar efficacy, safety, and tolerability, as well as comparable bioactive and total IGF-I response, as daily GH (0.067 mg/kg/day) in children born SGA.

South Asia has >50% of the global burden of low birth weight (LBW). The objective was to determine the extent to which maternal nutrition interventions commenced before conception or in the 1st trimester improved fetal growth in this region. This was a secondary analysis of combined newborn anthropometric data for the South Asian sites (India and Pakistan) in the Women First Preconception Maternal Nutrition Trial. Participants were 972 newborn of mothers who were poor, rural, unselected on basis of nutritional status, and had been randomized to receive a daily lipid-based micronutrient supplement commencing ≥3 months prior to conception (Arm 1), in the 1st trimester (Arm 2), or not at all (Arm 3). An additional protein-energy supplement was provided if BMI <20 kg/m2 or gestational weight gain was less than guidelines. Gestational age was established in the 1st trimester and newborn anthropometry obtained <48-hours post-delivery. Mean differences at birth between Arm 1 vs. 3 were length +5.3mm and weight +89g. Effect sizes (ES) and relative risks (RR) with 95% CI for Arm 1 vs. 3 were: length-for-age Z-score (LAZ) +0.29 (0.11-0.46, p = 0.0011); weight-for-age Z-score (WAZ) +0.22 (0.07-0.37, p = 0.0043); weight-to-length-ratio-for-age Z-score (WLRAZ) +0.27 (0.06-0.48, p = 0.0133); LAZ<-2, 0.56 (0.38-0.82, p = 0.0032); WAZ <-2, 0.68 (0.53-0.88, p = 0.0028); WLRAZ <-2, 0.76 (0.64-0.89, p = 0.0011); small-for-gestational-age (SGA), 0.74 (0.66-0.83, p<0.0001); low birth weight 0.81 (0.66-1.00, p = 0.0461). For Arm 2 vs. 3, LAZ, 0.21 (0.04-0.38); WAZ <-2, 0.70 (0.53-0.92); and SGA, 0.88 (0.79-0.97) were only marginally different. ES or RR did not differ for preterm birth for either Arm 1 vs. 3 or 2 vs. 3. In conclusion, point estimates for both continuous and binary anthropometric outcomes were consistently more favorable when maternal nutrition supplements were commenced ≥3 months prior to conception indicating benefits to fetal growth of improving women's nutrition in this population.

Recombinant human growth hormone (rhGH) therapy is the primary treatment for children born small for gestational age (SGA) who fail to show spontaneous catch-up growth by two or four years. While its effects on white adipose tissue are well-documented, this pilot study aimed to investigate its impact on the lipidome and the thermogenic and endocrine activities of brown adipose tissue (BAT) in SGA children following rhGH treatment. The study involved 11 SGA children divided into two groups: (a) SGA children who were not treated with rhGH ( n  = 4) and (b) SGA children who received rhGH treatment with Saizen ® ( n  = 7). This second group of seven SGA children was followed for 12 months after initiating rhGH treatment. Interventions included 12-hour fasting blood extraction and infrared thermography at baseline and 3 and 12 months post-treatment. Five appropriate-for-gestational-age (AGA) children served as controls. Exclusion criteria included endocrinological, genetic, or chronic diseases. Untargeted lipidomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS), and serum biomarker levels were measured using ELISA assays. Serum lipidomic analysis revealed that free fatty acids (FFAs) increased to levels close to those of the AGA group after three months of rhGH administration, including polyunsaturated fatty acids, correlating with reduced leptin levels. Elevated levels of 1a,1b-dihomo-PGJ2 and adrenic acid suggested potential aging markers. rhGH treatment also significantly reduced meteorin-like (METRNL) and monocyte chemoattractant protein-1 (MCP1) serum levels to control levels. rhGH influences the serum lipidome, promoting changes in maturation and metabolism. Further research is required to clarify the direct effects of rhGH on specific lipid species and batokines, potentially addressing metabolic disturbances linked to obesity and aging.

ObjectiveWe performed a randomised trial in very preterm, small for gestational age (SGA) babies to determine if prophylaxis with granulocyte macrophage colony stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). GM-CSF was associated with improved neonatal neutrophil counts, but no change in other neonatal or 2-year outcomes. As subtle benefits in outcome may not be ascertainable until school age we performed an outcome study at 5 years.Patients and methods280 babies born at 31 weeks of gestation or less and SGA were entered into the trial. Outcomes were assessed at 5 years to determine neurodevelopmental and general health status and educational attainment.ResultsWe found no significant differences in cognitive, general health or educational outcomes between 83 of 106 (78%) surviving children in the GM-CSF arm compared with 81 of 110 (74%) in the control arm. Mean mental processing composite (equivalent to IQ) at 5 years were 94 (SD 16) compared with 95 (SD 15), respectively (difference in means −1 (95%CI −6 to 4), and similar proportions were in receipt of special educational needs support (41% vs 35%; risk ratio 1.2 (95% CI 0.8 to 1.9)). Performance on Kaufmann-ABC subscales and components of NEPSY were similar. The suggestion of worse respiratory outcomes in the GM-CSF group at 2 years was replicated at 5 years.ConclusionsThe administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse neurodevelopmental, general health or educational outcomes at 5 years.Trial registration numberISRCTN42553489.

The prevalence of overweight and obesity amongst reproductive women has been increasing worldwide. Our aim was to compare pregnancy outcomes and infant neurocognitive development by different BMI classifications and investigate whether early pregnancy BMI was associated with risks of adverse outcomes in a Southwest Chinese population. We analysed data from 1273 women enrolled in the Complex Lipids in Mothers and Babies (CLIMB) randomized controlled trial in Chongqing, China. Maternal BMI was classified as underweight, normal weight and overweight/obese according to the Chinese, WHO Asian, and WHO European standards. For the adverse pregnancy outcomes, after adjustment for potential confounders, an underweight BMI was associated with increased risk of small for gestational age (SGA) babies, and an overweight/obese BMI was associated with increased risk of maternal gestational diabetes mellitus (GDM), caesarean section (C-section), macrosomia and large for gestational age (LGA) babies. For infant neurocognitive development, 1017 mothers and their children participated; no significant differences were seen in the Mental Development Index (MDI) or the Psychomotor Development Index (PDI) between the three BMI groups. Our findings demonstrate that abnormal early pregnancy BMI were associated with increased risks of adverse pregnancy outcomes in Chinese women, while early pregnancy BMI had no significant influence on the infant neurocognitive development at 12 months of age.

Background/Aims: An examination of the effects of up to 260 weeks of growth hormone (GH) therapy on metabolic parameters in Japanese children born small for gestational age (SGA). Methods: Data were analysed from a 156-week extension of a 104-week multicentre, randomised, double-blind, parallel-group trial. Sixty-five children born SGA (age 3-<8 years) received 33 μg/kg/day (n = 31, 64.5% male) or 67 μg/kg/day (n = 34, 58.8% male) GH for 260 weeks. Changes in metabolic parameters - glucose, insulin, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol - were recorded. Alterations in weight, body mass index standard deviation score (BMI SDS) and vital signs were also evaluated. Results: Over 260 weeks of GH treatment, a positive correlation between Δheight SDS and Δinsulin-like growth factor-I SDS was observed. Insulin and glucose levels were generally unaffected. Favourable changes in lipid profiles were recorded, which were maintained for the study duration. No adverse alterations in weight, BMI SDS or vital signs were noted. Conclusion: Long-term, continuous GH treatment in children born SGA appears to be efficacious, associated with potential benefits for several metabolic parameters and associated with no long-term safety concerns.

Background & objectives: A etiologically symmetric and asymmetric small for gestational age (SGA) infants are two distinct entities. In view of absence of longitudinal information on growth pattern of skinfold thicknesses (SFTs) among Indian infants, this study was conducted to assess the auxological dynamics of SFTs (sub-cutaneous fat) of symmetric and asymmetric SGA infants. Methods: Triceps, sub-scapular, biceps, mid-axillary and anterior thigh SFTs among full-term, 100 symmetric SGA, 100 asymmetric SGA and 100 appropriate for gestational age (AGA) infants were measured at one, three, six, nine and 12 months. Ponderal Index (PI) was used to categorize infants into symmetric SGA (PI ≥2.2 g/cm3) and asymmetric SGA (PI <2.2 g/cm3). Intra-group (symmetric vs. asymmetric), inter-group (SGA vs. AGA) and gender differences were quantified. Results: SFTs among symmetric, asymmetric SGA infants increased to attain peak by six months. Maximum fat deposition in SGA infants was noticed for triceps, minimum for mid-axillary SFT. Mean triceps and sub-scapular skinfolds were measured higher in symmetric SGA than in asymmetric infants. SGA infants had significantly (P≤0.05) thinner SFTs than AGA. Growth velocity for SFTs, among symmetric and asymmetric SGA, was measured maximum between one and three months, threreafter it declined and relatively, steepness of fall was maximum for mid-axillary SFT followed by sub-scapular SFT. Interpretation & conclusions: Thinner SFTs obtained for symmetric and asymmetric SGA as compared to AGA infants reveal their compromised adiposity and nutritional status. Comparatively, higher SFTs in symmetric than in asymmetric SGA infants appear to suggest that the former have a tendency to accumulate more fat, than the latter during infancy.

Background Sub-optimal maternal lipid levels during pregnancy may be implicated in the pathophysiological mechanisms leading to low birth weight (LBW) and small-for-gestational-age (SGA). We aimed to determine whether maternal lipid levels across pregnancy were associated with birth weight and the risks of LBW and SGA in rural Gambia. Methods This secondary analysis of the ENID trial involved 573 pregnant women with term deliveries. Plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglycerides (TG) were analyzed at enrolment (mean (SD) = 13.9 (3.3) weeks gestation), 20 and 30 weeks gestation as continuous variables and percentile groups. Regression models with adjustment for confounders were used to examine associations between gestational lipid levels and birth weight and the risks of LBW (birth weight < 2500 g) and SGA (<10th percentile INTERGROWTH-21ST for birth weight). Results There were 7.9% LBW and 32.5% SGA infants. At enrolment, every unit increase in HDL-c was associated with a 2.7% ( P  = 0.011) reduction in relative risk of LBW. At 20 weeks gestation, every unit increase in TC levels was associated with a 1.3% reduction in relative risk of LBW ( P  = 0.002). Low (<10th percentile) HDL-c at enrolment or at 20 weeks gestation was associated with a 2.6 ( P  = 0.007) and 3.0 ( P  = 0.003) times greater risk of LBW, respectively, compared with referent (10th─90th) HDL-c. High (>90th percentile) LDL-c at 30 weeks gestation was associated with a 55% lower risk of SGA compared with referent LDL-c ( P  = 0.017). Increased levels of TC (β = 1.3, P  = 0.027) at 20 weeks gestation and of TC (β = 1.2, P  = 0.006) and LDL-c (β = 1.5, P  = 0.002) at 30 weeks gestation were all associated with higher birth weight. Conclusions In rural Gambia, lipid levels during pregnancy were associated with infant birth weight and the risks of LBW and SGA. Associations varied by lipid class and changed across pregnancy, indicating an adaptive process by which maternal lipids may influence fetal growth and birth outcomes. Trial registration This trial was registered as ISRCTN49285450 on: 12/11/2009.

Background Delayed cord clamping is the standard of care in infants not requiring resuscitation; however effects of cord clamping strategies have not been evaluated systematically in small for gestational age (SGA) infants. The primary objective was to compare effects of delayed cord clamping (DCC) and early cord clamping (ECC) on serum ferritin at 3 months in SGA infants born at ≥35 weeks. The secondary objectives were to compare hematological parameters, clinical outcomes in neonatal period and growth at 3 months of age. Methods All eligible infants with fetal growth restriction were randomized to two groups, DCC at 60 s or ECC group in which the cord was clamped immediately after birth. Results Total of 142 infants underwent randomization and subsequently 113 infants underwent definite inclusion. At 3 months, the median (IQR) serum ferritin levels were higher in DCC group, compared to ECC; 86 ng/ml (43.35–134.75) vs 50.5 ng/ml (29.5–83.5), p  = 0.01. Fewer infants had iron deficiency in DCC group compared to ECC group; 9 (23.6%) vs 21 (47.7%), p  = 0.03 [NNT being 4; 95% CI (2–25)].The proportion of infants with polycythemia was significantly higher in DCC group; 23 (41.81) % vs 12 (20.6%), p = 0.01. There was no difference in proportion of infants with symptomatic polycythemia or those who underwent partial exchange transfusions. Clinical outcomes and mortality were similar. Conclusions DCC improves iron stores in SGA infants ≥35 weeks at 3 months of age without increasing the risk of symptomatic polycythemia, need for partial exchange transfusions or morbidities associated with polycythemia. Trial registration Our trial was retrospectively registered on 29th May 2015 through Clinical trials registry India. Registration number: CTRI 2015/05/005828 .