Onset of puberty and near adult height in short children born small for gestational age and treated with GH: Interim analysis of up to 10 years of treatment in Japan.

The safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children born small for gestational age (SGA) were evaluated based on interim data analysis from a clinical study, including the findings concerning the influence on the onset of puberty and subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at baseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm and 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6 in boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and 9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of puberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children. Treatment-related adverse events were generally mild to moderate in severity; however, adenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject had jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable changes in HbA1c levels were observed, and the levels remained within the reference range. We have confirmed the safety and effectiveness of long-term GH treatment through this ongoing clinical study.

Efficacy and Safety of Up to 8 Years of Long-term Growth Hormone Treatment in Short Children Born Small for Gestational Age in Japan: Analysis of the Subpopulation According to the Japanese Guideline.

The efficacy and safety of 8 yr of GH treatment was assessed in 44 Japanese children with small for gestational age (SGA) short stature who met the criteria for GH treatment initiation (height SD score (SDS) <-2.5 SD) of the Japanese guidelines. Height SDS in subjects improved throughout the study period, and average height SDS improved from -3.5 to -1.6 and from -3.4 to -1.9 in the 0.033/0.067 mg and 0.067/0.067 mg groups, respectively, after 8 yr of GH treatment. Delta height SD was approximately +2 after 4 yr of treatment, and ∆ IGF-1 showed a significant positive correlation with ∆ height SD after both 1 and 2 yr (r = 0.415 and 0.488, respectively) of treatment. There was no correlation between the age at the start of treatment and age at onset of puberty, and the median age at the onset of puberty in the subjects was almost the same as that in healthy children. In conclusion, clinically significant improvements in the height SDS was confirmed in short children born SGA after 8 yr of GH treatment without any safety problems.

Long-term efficacy and safety of two doses of growth hormone in short Japanese children born small for gestational age.

BACKGROUND/AIMS: To investigate the long-term efficacy and safety of two doses (33 and 67 µg/kg/day) of growth hormone (GH) in short Japanese children born small for gestational age (SGA). METHODS: 96 children born SGA (age 3 to <8 years) were randomized to GH at 33 or 67 µg/kg/day for 104 weeks, or to an untreated control (UC) group for 52 weeks. After 52 weeks, the UC group was randomized to GH at a dose of 33 or 67 µg/kg/day for a 156-week extension study. Initial treatment groups continued unchanged for the extension phase. Efficacy was evaluated by change in height SDS for chronological age from baseline to 208/260 weeks. RESULTS: After 208 weeks, change in height SDS from baseline (least square (LS) means (SE)) was 1.01 (0.47) and 1.99 (0.67) in the UC 33 and UC 67 µg/kg/day groups, respectively. After 260 weeks, change in height SDS from baseline was 1.22 (0.51) and 2.01 (0.64) in the 33 and 67 µg/kg/day groups, respectively. Insulin-like growth factor-1 levels were significantly higher in the groups receiving 67 µg/kg/day but largely remained within normal limits (-2 to +2 SDS). CONCLUSION: Long-term continuous GH treatment was well tolerated and effective in improving height SDS. Improvements were dose-dependent and significantly higher at 67 than 33 µg/kg/day.

Outcomes of very-low-birthweight infants at 3 years of age born in 2003-2004 in Japan.

BACKGROUND: The aim of this study was to describe and compare neurodevelopmental outcomes with birthweight (BW) groups at 250-g intervals of very-low-birthweight (VLBW) infants at 3 years of age in a multicenter cohort in Japan. METHODS: A total of 3104 VLBW infants born in 2003 and 2004 registered in a NICU-network database were followed in the study. Neurodevelopmental impairment (NDI) was defined as any of the following impairments: cerebral palsy, unilateral or bilateral blindness, severe hearing impairment, or developmental delay; a developmental quotient (DQ) <70 measured using the Kyoto Scale of Psychological Development test or judged by physicians in infants without the test. RESULTS: A total of 257 infants died and follow-up data were obtained from 1826 infants. Of the 1826 infants, 155 (8.5%) had cerebral palsy, 25 (1.4%) had visual impairment, and 12 (0.7%) had hearing impairment. Of the 1197 infants in whom DQ was measured, 184 (15.4%) had DQ < 70. The proportion of NDI in the evaluated infants was 19.2% (n= 350), ranging from 11.9% (BW 1251-1500 g) to 42.0% (BW ≤ 500 g). Odds ratios (95%CI) of NDI or death against the group BW 1251-1500 g were 20.62 (13.29-31.97) in BW ≤ 500 g, 7.25 (5.45-9.64) in BW 501-750 g, 2.85 (2.12-3.82) in BW 751-1000 g and 1.18 (0.85-1.64) in BW 1001-1250 g. CONCLUSION: The increasing proportion of NDI or death, an indicator of adverse outcome, was associated with decrement in the BW of the groups. Although we have to consider a bias due to loss of follow-up data, the incidence of NDI was similar to previous overseas cohort studies despite the higher survival proportion in our study.

Neonatal correlates of adverse outcomes in very low-birthweight infants in the NICU Network.

BACKGROUND: The aim of the present study was to explore the relationships among neonatal morbidity, interventions and death or adverse neurodevelopmental outcomes in very low-birthweight (VLBW) infants. METHODS: Subjects were infants with birthweight ≤ 1500 g who were cared for in the tertiary neonatal intensive care units in Japan. Multiple logistic regression analysis was performed to examine the odds ratios (OR) and 95% confidence intervals (CI) of neonatal factors for death or cerebral palsy (CP) and death or developmental delay (developmental quotient <70 or delay judged by physicians) at 3 years of age after adjusting for biological and prenatal variables. RESULTS: Of the 3104 subjects, 257 died and 1826 were evaluated at 3 years of age. Cystic periventricular leukomalacia (PVL; OR, 23.9; 95%CI: 11.0-51.7), gastrointestinal perforation (OR, 8.5; 95%CI: 2.8-25.4), intraventricular hemorrhage (IVH) grade 3 or 4 (OR, 3.1; 95%CI: 1.3-7.2) and sepsis (OR, 2.6; 95%CI: 1.4-4.8) were neonatal factors significantly associated with an increased risk of death or CP. Significant correlates with death or developmental delay were cystic PVL (OR, 7.9; 95%CI: 3.7-16.8), gastrointestinal perforation (OR, 6.3; 95%CI: 1.9-20.8), sepsis (OR, 2.8; 95%CI: 1.6-4.8), IVH grade 3 or 4 (OR, 2.6; 95%CI: 1.2-5.7), chronic lung disease at 36 weeks of corrected gestational age (OR, 1.6; 95%CI: 1.1-2.4) and treatment for retinopathy of prematurity (ROP; OR, 1.5; 95%CI: 1.0-2.3). CONCLUSION: Cystic PVL, gastrointestinal perforation, IVH and sepsis correlated with both death or CP and death or developmental delay in VLBW infants. Chronic lung disease at 36 weeks and treatment for ROP were associated with death or developmental delay, but not with death or CP.

Efficacy and safety of growth hormone treatment in children born small for gestational age in Japan.

Growth-promoting effects and safety of growth hormone (GH) treatment in prepubertal short-statured children born small for gestational age (SGA) were evaluated in a multicenter, open-label, randomized parallel-group comparison study. Patients were randomized to two dose groups; 34 and 33 patients received GH at 0.033 and 0.067 mg/kg/day for one year, respectively. The increase of the mean height velocity standard deviation score (SDS) was significantly (p <0.0001) higher in the 0.067-mg group (from -1.4 to 4.7) than that in the 0.033-mg group (-1.9 to 2.6). A significant (p <0.0001) increase in the mean height SDS was established in the 0.067-mg group; increases of -3.1 to -2.5 vs -3.1 to -2.2 in the 0.033- and 0.067-mg groups, respectively. The trial was non-eventful. Oral glucose tolerance tests indicated a mostly normal pattern of plasma glucose before and after 12-month GH treatment. The growth-promoting effect was significantly higher with GH treatment at 0.067 mg/kg/day.

Developmental characteristics of very low-birthweight infants at 18 months' corrected age according to birthweight.

BACKGROUND: The objective of the present study was to describe developmental profiles of very low-birthweight (VLBW) infants compared by birthweight, because those of infants with birthweight <750 g might be different from other VLBW infants. METHODS: VLBW infants from four medical centers were followed at each site with the same protocol at 18 months' corrected age. The protocol by the Society for the Study of Follow up for High-Risk Infants, which includes a standardized developmental test, the Kyoto Scale of Psychological Development (KSPD), was used. Five hundred and sixty-four VLBW infants without neurological or neurosensory impairment were divided into four groups using 250 g birthweight intervals and outcomes were compared between the four groups. RESULTS: Developmental characteristics of extremely low-birthweight infants (birthweight <750 g) in comparison with other VLBW infants were as follows: (i) more infants were judged clumsy in their fine motor skills; (ii) fewer were able to speak meaningful words although they were able to understand oral simple orders; (iii) developmental quotients (DQ) of KSPD was significantly lower; and (iv) more infants were judged as hyperactive. CONCLUSION: Developmental profiles of VLBW infants without major handicaps at 18 months' corrected age correlated significantly with their birthweight sequence. These results provide useful information on developmental outcomes of VLBW infants.

Impact of being small-for-gestational age on survival and long-term outcome of extremely premature infants born at 23-27 weeks' gestation.

AIM: To evaluate factors affecting survival and long-term outcome of extremely premature infants and to determine whether small for gestational age (SGA) status is an additional risk factor. METHODS: Survival was analyzed in 193 infants born between 23 and 27 weeks of gestational age (GA) and compared between SGA (n=43) and appropriate for gestational age (AGA) infants. Long-term outcome was assessed in 123 infants at six years of chronological age by neurological evaluation and cognitive tests. RESULTS: The long-term survival rates were 72.1% for SGA and 84.0% for AGA infants. Significant independent factors affecting survival were GA (OR 1.79 for one week advance, 95% CI 1.36-2.34) and SGA (OR 0.42, 95% CI 0.18-0.997) in comparison with AGA. There were no significant differences in rates of cerebral palsy or mental retardation, 12.0% and 24.0% in SGA, 14.3% and 17.3% in AGA, respectively. Fifty-two percent of SGA and 70% of AGA infants had intact long-term outcome. The perinatal factor found to affect the intact long-term outcome was RDS with surfactant therapy (OR 0.17, 95% CI 0.07-0.45). CONCLUSION: SGA status as well as short gestation had significant effects on survival. Respiratory complications after birth had a larger detrimental effect on long-term outcome than whether the infant was SGA or AGA.

Longitudinal follow-up of height up to five years of age in infants born preterm small for gestational age; comparison to full-term small for gestational age infants.

OBJECTIVE: This aims to conduct a comparative study of the height catch-up rate in preterm small for gestational age (SGA) infants during early childhood by gestational age and identify the factors affecting short stature in comparison to full-term SGA infants. METHODS: 449 SGA infants (214 full-term infants, 73 infants with gestation of less than 32 weeks, and 162 infants with gestation of more than 32 weeks but less than 37 weeks) from 25 institutions in Japan were assessed for catch-up (> or = -2SD) rate in growth by measuring for length/height at 1 year, 3 years and 5 years of age and the risk factors for no catch-up (< -2SD) at 5 years. RESULTS: The overall length/height catch-up rate was 68% at 1 year, 89% at 3 years and 88% at 5 years. The catch-up rate at 3 and 5 years of age in the group with gestation of less than 32 weeks had a rate of 74%, which was significantly less than the other two groups (approximately 90%). A significant factor associated with short stature at 5 years in the group with gestation of less than 32 weeks was the lower length SD score at time of birth, and for preterm infants born more than 32 weeks of gestation and full-term infants, significant factors were the lower maternal height and head circumference at birth. CONCLUSION: SGA infants born less than 32 weeks of gestation had a higher risk of no catch-up and different factors affecting catch-up compared to preterm SGA infants of gestation more than 32 weeks and full-term SGA infants.