Novel type of references for BMI aligned for onset of puberty - using the QEPS growth model.

OBJECTIVES: Despite inter-individual variations in pubertal timing, growth references are conventionally constructed relative to chronological age (C-age). Thus, they are based on reference populations containing a mix of prepubertal and pubertal individuals, making them of limited use for detecting abnormal growth during adolescence. Recently we developed new types of height and weight references, with growth aligned to age at onset of the pubertal growth spurt (P-age). Here, we aim to develop a corresponding reference for pubertal BMI. METHODS: The QEPS-height and weight models were used to define a corresponding QEPS-BMI model. QEPS-BMI was modified by the same individual, constitutional weight-height-factor (WHF) as computed for QEPS-weight. QEPS-BMI functions were computed with QEPS weight and height functions fitted on longitudinal measurements from 1418 individuals (698 girls) from GrowUp1990Gothenburg cohort. These individual BMI functions were used to develop BMI references aligned for height at AgeP5; when 5% of specific puberty-related (P-function) height had been attained. Pubertal timing, stature at pubertal onset, and childhood BMI, were investigated in subgroups of children from the cohort GrowUp1974Gothenburg using the new references. RESULTS: References (median, standard deviation score (SDS)) were generated for total BMI (QEPS-functions), for ongoing prepubertal growth (QE-function) vs C-age, and for total BMI and separated into BMI specific to puberty (P-function) and BMI gain from ongoing basic growth (QES-functions), allowing individual growth to be aligned based on P-age. Growth in basic BMI was greater than average for children categorized as tall and/or with high-BMI at puberty-start. In children categorized as short at puberty-start, P-function-related-BMI was greater than average. CONCLUSIONS: Use of these new pubertal BMI references will make it possible for the first time to consider individual variations owing to pubertal timing when evaluating BMI. This will improve the detection of abnormal changes in body composition when used in combination with pubertal height and weight references also abnormal growth. Other benefits in the clinic will include improved growth monitoring during treatment for children who are overweight/obese or underweight. Furthermore, in research settings these new references represent a novel tool for exploring human growth.

Growth pattern evaluation of the Edinburgh and Gothenburg cohorts by QEPS height model.

BACKGROUND: The QEPS-growth-model, developed and validated in GrowUp-Gothenburg cohorts, used for developing growth references and investigating healthy/pathological growth, lacks external validation from other longitudinal cohorts of healthy individuals. AIM: To investigate if the QEPS-model can fit the longitudinal Edinburgh growth study of another design than GrowUp-Gothenburg cohorts, and to compare growth patterns in the individuals born in mid-1970s in North-Western Europe. METHODS: Longitudinal growth data were obtained from the Edinburgh and the GrowUp1974Gothenburg cohorts. The QEPS-model was used to describe length/height from birth to adult height with confidence interval, and the multivariable regression model for estimating the contribution of the different QEPS-functions to adult height. RESULTS: The QEPS-model fitted the Edinburgh cohort well, with high accuracy, and low confidence intervals indicating high precision. Despite 3 cm shorter stature (less QE-function growth) in Scottish children, the growth patterns of the cohorts were similar, especially for specific pubertal growth. The contribution to adult height from different QEPS functions was similar. CONCLUSION: The QEPS-model is validated for the first time in a longitudinal study of healthy individuals of another design and found to fit with high accuracy and precision. The Scottish and Western-Swedish cohorts born in mid-1970s showed similar growth patterns for both sexes, especially pubertal growth. IMPACT: For the first time, the QEPS height model was used and found to fit another longitudinal cohort of healthy individuals other than the Swedish longitudinal cohorts. With large numbers of individual measurements in each growth phase, the QEPS model calculates growth estimates with narrow confidence intervals (high precision) and high accuracy. The two different cohorts born in the mid-1970s from Scotland and Western Sweden have similar growth patterns, despite a 3 cm difference in adult height.

Novel type of references for weight aligned for onset of puberty - using the QEPS growth model.

BACKGROUND: Growth references are traditionally constructed relative to chronological age, despite inter-individual variations in pubertal timing. A new type of height reference was recently developed allowing growth to be aligned based on onset of pubertal height growth. We here aim to develop a corresponding reference for pubertal weight. METHODS: To model QEPS-weight, 3595 subjects (1779 girls) from GrowUp1974Gothenburg and GrowUp1990Gothenburg were used. The QEPS-height-model was transformed to a corresponding QEPS-weight-model; thereafter, QEPS-weight was modified by an individual, constitutional weight-height-factor. Longitudinal weight and length/height measurements from 1418 individuals (698 girls) from GrowUp1990Gothenburg were then used to create weight references aligned for height at pubertal onset (the age at 5% of P-function growth, AgeP5). GrowUp1974Gothenburg subgroups based on pubertal timing, stature at pubertal onset, and childhood body composition were assessed using the references. RESULTS: References (median, SDS) for total weight (QEPS-functions), weight specific to puberty (P-function), and weight gain in the absence of specific pubertal growth (basic weight, QES-functions), allowing alignment of individual growth based on age at pubertal onset. For both sexes, basic weight was greater than average for late maturing, tall and high-BMI subgroups. The P-function-related weight was greater than average in short and lower than average in tall children, in those with high BMI, and in girls but not boys with low BMI. CONCLUSIONS: New pubertal weight references allow individual variations in pubertal timing to be taken into consideration when evaluating growth. When used together with the comparable pubertal height reference, this will improve growth monitoring in clinical practice for identifying abnormal growth and serve as a valuable research tool providing insight into human growth.

Prediction of Adult Height by Machine Learning Technique.

CONTEXT: Prediction of AH is frequently undertaken in the clinical setting. The commonly used methods are based on the assessment of skeletal maturation. Predictive algorithms generated by machine learning, which can already automatically drive cars and recognize spoken language, are the keys to unlocking data that can precisely inform the pediatrician for real-time decision making. OBJECTIVE: To use machine learning (ML) to predict adult height (AH) based on growth measurements until age 6 years. METHODS: Growth data from 1596 subjects (798 boys) aged 0-20 years from the longitudinal GrowUp 1974 Gothenburg cohort were utilized to train multiple ML regressors. Of these, 100 were used for model comparison, the rest was used for 5-fold cross-validation. The winning model, random forest (RF), was first validated on 684 additional subjects from the 1974 cohort. It was additionally validated using 1890 subjects from the GrowUp 1990 Gothenburg cohort and 145 subjects from the Edinburgh Longitudinal Growth Study cohort. RESULTS: RF with 51 regression trees produced the most accurate predictions. The best predicting features were sex and height at age 3.4-6.0 years. Observed and predicted AHs were 173.9 ±â€…8.9 cm and 173.9 ±â€…7.7 cm, respectively, with prediction average error of -0.4 ±â€…4.0 cm. Validation of prediction for 684 GrowUp 1974 children showed prediction accuracy r = 0.87 between predicted and observed AH (R2 = 0.75). When validated on the 1990 Gothenburg and Edinburgh cohorts (completely unseen by the learned RF model), the prediction accuracy was r = 0.88 in both cases (R2 = 0.77). AH in short children was overpredicted and AH in tall children was underpredicted. Prediction absolute error correlated negatively with AH (P < .0001). CONCLUSION: We show successful, validated ML of AH using growth measurements before age 6 years. The most important features for prediction were sex, and height at age 3.4-6.0. Prediction errors result in over- or underestimates of AH for short and tall subjects, respectively. Prediction by ML can be generalized to other cohorts.

Swedish references for weight, weight-for-height and body mass index: The GrowUp 1990 Gothenburg study.

AIM: To update the Swedish references for weight, weight-for-height and body mass index (BMI) considering the secular trend for height but not including that for weight. METHODS: Longitudinal measures of height and weight were obtained (0-18 years) from 1418 (698 girls) healthy children from the GrowUp 1990 Gothenburg cohort born at term to non-smoking mothers and Nordic parents. A total of 145 individuals with extreme BMI value vs GrowUp 1974 BMI SDS reference were excluded (0-2 years: ±4SDS, 2 < years: -3SDS, +2.3SDS). References were constructed using the LMS method. RESULTS: The updated weight reference became similar to the GrowUp 1974 Gothenburg reference: BMI increased rapidly up to lower levels in the 1990 cohort during infancy/early childhood, similar in both groups in late childhood/adolescence, despite lower values at +2SDS. Compared with the WHO weight standard, median and -2SDS weight values were higher for the 1990 cohort, whereas +2SDS values were lower, resulting in narrower normal range. Median values were greater and ±2SDS narrower for the 1990 vs the WHO weight-for-height reference. International Obesity Task force (IOTF) BMI lines for definitions for over- and underweight were added. CONCLUSION: We present updated references for weight, weight-for-height and BMI, providing a healthy goal for weight development when monitoring growth within healthcare settings.

The pubertal growth spurt is diminished in children with severe obesity.

BACKGROUND: At the population level, there is a negative linear correlation between childhood body mass index (BMI) and pubertal height gain. However, in children with obesity, there are no studies showing whether the severity of obesity affects pubertal height gain. Moreover, how obesity in childhood affects pubertal timing is controversial, especially in boys. We aimed to investigate the impact of severe obesity in childhood on the pubertal growth spurt in both sexes. METHODS: The study group consisted of 68 patients (32 boys) with childhood onset obesity followed in a Spanish university hospital. The QEPS growth model was used to calculate pubertal growth function estimates for each individual. The highest individual prepubertal BMI SDS value was related to the age at onset of pubertal growth and pubertal height gain. Results were compared to analyses from individuals in a community-based setting (n = 1901) with different weight status. RESULTS: A higher peak BMI in childhood was associated with less specific pubertal height gain in children with moderate-to-extreme obesity. For boys, the higher the BMI, the earlier the onset of pubertal growth. For girls with obesity, this correlation was not linear. CONCLUSIONS: Obesity in childhood impairs the pubertal growth spurt in a severity-related fashion. IMPACT: The higher the BMI in childhood, the lower the pubertal height gain in children with moderate-to-extreme obesity. For boys with obesity, the higher the BMI, the earlier the onset of pubertal growth. The results contribute to the research field of how weight status in childhood is related to pubertal timing and pubertal growth. The results have implications for understanding how childhood obesity is related to further growth.

A new type of pubertal height reference based on growth aligned for onset of pubertal growth.

Objectives Growth references of today traditionally describe growth in relation to chronological age. Despite the broad variation in age of pubertal maturation, references related to biological age are lacking. To fill this knowledge gap, we aimed to develop a new type of pubertal height reference for improved growth evaluation during puberty, considering individual variation in pubertal timing. Methods Longitudinal length/height measures were obtained from birth to adult height in 1,572 healthy Swedish children (763 girls) born at term ∼1990 to nonsmoking mothers and Nordic parents, a subgroup of GrowUp1990Gothenburg cohort. A total height reference was constructed from Quadratic-Exponential-Puberty-Stop (QEPS)-function-estimated heights from individual height curves that had been aligned for time/age at onset of pubertal growth (5% of P-function growth). References that separated growth into specific pubertal heightSDS (P-function growth) and basic heightSDS (QES-function growth) were also generated. Results References (cm and SDS) are presented for total height, and height subdivided into that specific to puberty and to basic growth arising independently of puberty. The usefulness of the new pubertal growth reference was explored by identifying differences in the underlying growth functions that translate into differences in pubertal height gain for children of varying body mass, height, and with different pubertal timings. Conclusions A new type of height reference allowing alignment of individual growth curves, based on the timing of the pubertal growth spurt was developed using QEPS-model functions. This represents a paradigm shift in pubertal growth research and growth monitoring during the adolescent period.

Altered umbilical sex steroids in preterm infants born small for gestational age.

Background: Boys born small for gestational age (SGA) are at increased risk of testicular dysgenesis syndrome, and girls born SGA face the risk of polycystic ovary syndrome later in life. Our aim was to study whether neonates born SGA have an altered profile of steroid hormones at birth.Materials and methods: A total of 168 singletons (99 boys, 69 girls) born at 32.0-36.9 gestational weeks were recruited to a population-based, university hospital, single-center study. Of these, 31 infants (17 boys, 14 girls) were born SGA. The concentrations of dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, cortisone, and cortisol were analyzed in umbilical cord serum with mass spectrometry.Results: Girls born SGA had higher levels of androstenedione than girls born appropriate for gestational age (AGA) (4.0 versus 2.6 nmol/L, p = .002). Boys born SGA had lower levels of estrone than boys born AGA (33 822 versus 62 471 pmol/L, p = .038). Infants born SGA had lower levels of cortisone than infants born AGA, both in girls (340 versus 579 nmol/L, p = .010) and in boys (308 versus 521 nmol/L, p = .045). Furthermore, boys born SGA had a higher cortisol/cortisone ratio than boys born AGA (0.41 versus 0.25, p = .028). Gestational age correlated with DHEAS (boys r = 0.48, p = .000, girls r = 0.35, p = .013), and cortisol (boys r = 0.48, p = .000, girls r = 0.29, p = .039).Conclusions: In moderate-to-late preterm infants born SGA, we observed a different steroid hormone profile in cord serum. Girls born SGA show increased levels of androstenedione and boys born SGA show decreased levels of estrone in cord serum, which could be related to placental aromatase deficiency in intrauterine growth restriction.

A new Swedish reference for total and prepubertal height.

AIM: We aimed to develop up-to-date references with standard deviation scores (SDS) for prepubertal and total height. METHODS: Longitudinal length/height measures from 1572 healthy children (51.5% boys) born at term in 1989-1991 to non-smoking mothers and Nordic parents were obtained from the GrowUp 1990 Gothenburg cohort. A total height SDS reference from birth to adult height was constructed from Quadratic-Exponential-Pubertal-Stop (QEPS) function estimated heights based on individual growth curves. A prepubertal height SDS reference, showing growth trajectory in the absence of puberty, was constructed using the QE functions. RESULTS: The total height reference showed taller prepubertal mean heights (for boys 1-2 cm; for girls 0.5-1.0 cm) with a narrower normal within ± 2SDS range vs the GrowUp 1974 Gothenburg reference. Adult height was increased by + 0.9 cm for women (168.6 cm) and by + 1.6 cm for men (182.0 cm). Height in children growing at -2SDS (the cut-off used for referrals) differed up to 2 cm vs the GrowUp 1974 Gothenburg reference, 3 cm vs Swedish 1981 references and World Health Organisation (WHO) 0-5 years standard, and 6-8 cm vs the WHO 5-19 years reference. CONCLUSION: Up-to-date total and prepubertal height references offer promise of improved growth monitoring compared with the references used in Sweden today.

Nordic populations are still getting taller - secular changes in height from the 20th to 21st century.

AIM: The study aims to investigate secular changes in adult height among Nordic reference populations during the last four decades and in parents of Swedish study participants, and to study during which growth phase(s) infancy, childhood or puberty changes in height and tempo occurred. METHODS: Length and height data were obtained from publications on populations used as current and previous national height references in Denmark, Finland, Norway and Sweden. Measurements from birth until adult height and original parental heights of participants in Swedish reference populations born 1956, 1974, and 1990 were used. RESULTS: Adult height has increased progressively in Nordic populations born in 1950s-1990s; for females by 6 mm/decade Norway, 4 mm; Sweden, 6 mm; Finland and Denmark, 7 mm; for males by 9 mm/decade, in Sweden, 5 mm; Finland, 7 mm; Denmark 8 mm; Norway, 15 mm. This was due to more growth during childhood despite earlier timing of mid-puberty. Heights of Swedish parents born 1920s-1960s increased 11 mm/decade for mothers, 14 mm/decade for fathers. CONCLUSION: The Nordic countries comprise some of the tallest populations in the world yet continue to show a positive secular change in adult height alongside a faster tempo of growth by earlier timing of puberty, highlighting the need to regularly update national height references.

Estimating secular changes in longitudinal growth patterns underlying adult height with the QEPS model: the Grow Up Gothenburg cohorts.

BACKGROUND: Over the past 150 years, humans have become taller, and puberty has begun earlier. It is unclear if these changes are continuing in Sweden, and how longitudinal growth patterns are involved. We aimed to evaluate the underlying changes in growth patterns from birth to adulthood by QEPS estimates in two Swedish cohorts born in 1974 and 1990. METHODS: Growth characteristics of the longitudinal 1974 and 1990-birth cohorts (n = 4181) were compared using the QEPS model together with adult heights. RESULTS: There was more rapid fetal/infancy growth in girls/boys born in 1990 compared to 1974, as shown by a faster Etimescale and they were heavier at birth. The laterborn were taller also in childhood as shown by a higher Q-function. Girls born in 1990 had earlier and more pronounced growth during puberty than girls born in 1974. Individuals in the 1990 cohort attained greater adult heights than those in the 1974 cohort; 6 mm taller for females and 10 mm for males. CONCLUSION: A positive change in adult height was attributed to more growth during childhood in both sexes and during puberty for girls. The QEPS model proved to be effective detecting small changes of growth patterns, between two longitudinal growth cohorts born only 16 years apart.

Insight into human pubertal growth by applying the QEPS growth model.

BACKGROUND: Computerized mathematical models describing absolute and relative individual growth during puberty in both cm and standard deviation (SD)-scores are lacking. The present study aimed to fill this gap, by applying the QEPS-model that delineates mathematically the specific pubertal functions of the total growth curve. METHODS: Study population used was the individual growth curves of the longitudinally followed cohort GrowUp1974 Gothenburg (n = 2280). The QEPS-model describes total height as (T)otal-function: a combination of four shape-invariant growth functions, modified by time-scale and height-scale parameters: a (Q)uadratic-function for the continuous growth from fetal life to adulthood; a negative (E)xponential-function adds the rapid, declining fetal/infancy growth; a (P)ubertal-function the specific pubertal growth spurt; a (S)top-function the declining growth until adult height. A constructed variable, MathSelect, was developed for assessing data-quality. CIs and SD-scores for growth estimates were calculated for each individual. QEPS-model estimates used for pubertal growth; from the T-function: onset of puberty as minimal height velocity (AgeT ONSET ); mid-puberty as peak height velocity (AgeT PHV ); end of puberty as height velocity decreased to 1 cm/year (AgeT END ); duration of different intervals and gain (AgeT ONSET-END and Tpubgain); from the P-function: onset of puberty, estimated as growth at 1% or 5% (AgeP1 , AgeP5); mid-puberty as 50% (AgeP50) and PHV (AgeP PHV ); end of pubertal growth at 95 or 99% (AgeP95, AgeP99); duration of different intervals and pubertal gain (Ppubgain; P max ); from the QES-function: gain (QESpubgain) . RESULTS: Application of these mathematical estimates for onset, middle and end of puberty of P-function, QES-function, and T-function during puberty showed: the later the onset of puberty, the greater the adult height; pubertal gain due to the P-function growth was independent of age at onset of puberty; boys had higher total gain during puberty due to P-function growth than to QES-function growth; for girls it was reversed. CONCLUSIONS: QEPS is the first growth model to provide individualized estimates of both the specific pubertal growth function and the total growth during puberty, with accompanying SD-scores and Cis for each individual. These QEPS-derived estimates enable more in-depth analysis of different aspects of pubertal growth than previously possible.

Declining Well-Being in Young Swedes Born in 1990 Versus 1974.

PURPOSE: Well-being is affected by the environment, including societal changes. In this study, specific dimensions of well-being were compared in two cohorts of Swedish adolescents born 16 years apart. METHODS: Two groups of 18-year-olds, "Grow up Gothenburg" 1974 and 1990 birth cohorts, completed a self-reported questionnaire including the Gothenburg Well-Being in adolescence scale (GWBa). In addition, height and weight were measured, resulting in 4,362 participants (1974 birth cohort) and 5,151 participants (1990 birth cohort) with age, height, weight, and well-being data. The GWBa consists of a total score and five dimensions: mood, physical condition, energy, self-esteem, and stress balance. RESULTS: Total well-being was significantly lower in the later-born cohort, and the greatest difference was seen for the dimension stress balance (feeling calm, unconcerned, unstressed, and relaxed), although effect sizes were modest. In both boys and girls, well-being was lower for all dimensions in the later-born cohort, with the exception of Self-esteem in girls, which was higher in the later-born cohort. In both cohorts, boys reported higher well-being than girls for all dimensions. The mean body mass index z-score was higher in boys from the later-born cohort, but after adjusting for weight status, the differences in well-being between the cohorts persisted. CONCLUSIONS: Well-being was lower in the later-born cohort, particularly for the dimension stress balance. Differences were not explained by the shift in weight status indicating that other societal changes have had an impact on well-being levels. Managing high levels of stress might be an area of intervention in adolescents for improved well-being.

Pubertal height gain is inversely related to peak BMI in childhood.

BACKGROUND: Childhood BMI may influence subsequent growth in height as well as the timing of puberty. The aim of the present study was to investigate associations between BMI in childhood and subsequent height gain/pubertal growth. METHODS: Longitudinal growth data were used (GrowUp1990Gothenburg cohort, n = 1,901). The QEPS growth-model was used to characterize height gain in relation to the highest BMISDS value between 3.5 and 8 y of age. Children were defined as overweight/obese (OwOb) or normal weight/underweight (NwUw), using the 2012 International Obesity Task Force criteria. RESULTS: A negative association between childhood BMISDS and pubertal height gain was observed. Already at birth, OwOb children were heavier than NwUw children, and had a greater height velocity during childhood. Onset of puberty was 3.5/3.0 mo earlier in OwOb girls/boys, and they had 2.3/3.1 cm less pubertal height gain from the QEPS-models specific P-function than NwUw children. Adult height was not related to childhood BMI. CONCLUSION: We found that pubertal height gain was inversely related to peak BMI in childhood. Higher childhood BMISDS was associated with more growth before onset of puberty, earlier puberty, and less pubertal height gain, resulting in similar adult heights for OwOb and NwUw children.

Modelling individual longitudinal human growth from fetal to adult life - QEPS I.

BACKGROUND: Only one mathematical model to date describes human growth and its different phases from fetal life until adult height. AIM: To develop a model describing growth from fetal life to adult height taking maturation/biological tempo into consideration. SUBJECTS: The model was developed based on longitudinal mean height values obtained from published growth references for a cohort of 3650 healthy Swedish children followed from birth circa 1974 until adult height combined with birth-length for circa 400 000 healthy infants born 1990-1995. RESULTS: The QEPS-model for individual growth was constructed with a combination of four basic shape-invariant growth functions: a quadratic Q-function and a negative exponential E-function, both started during fetal life, 8 months before birth; the E-function levelled off after birth, whereas the Q-function continued until end of growth. A specific nonlinear pubertal P-function started at onset of puberty, and a stop S-function ended growth according to both the Q-function continuing during puberty and the specific P-function. For each function, an individual height-scale parameter was defined, and for the E- and P-functions, a time-scale parameter; giving six modifying parameters in total. In addition standardized proportional scores were used for biological interpretations. The QEPS-model was used to fit and generate mathematical functions suitable to describe the growth of the healthy population of Swedish children; thereafter, the model was modified using four height-scale parameters to model individual height in cm, and two time-scale parameters to adjust for the individual tempo of growth. Individual confidence intervals were calculated for all parameters. CONCLUSIONS: A new shape-invariant growth model, QEPS, was developed, that requires only four basic growth functions to describe the total pattern of growth in height from fetal life to adult height, with addition of height- and time-scale parameters describing individual growth. The model can describe a wide variety of growth curves. Moreover, it is the first model to provide confidence intervals which enable us to describe the precision/quality of individual parameters.

Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics.

OBJECTIVE: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. DESIGN AND SETTING: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (ISS) or born small for gestational age (SGA). PARTICIPANTS: The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). MAIN OUTCOME MEASURES: Death. RESULTS: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001). CONCLUSIONS: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

Low birth weight is a risk factor for severe retinopathy of prematurity depending on gestational age.

OBJECTIVE: To evaluate the impact of low birth weight as a risk factor for retinopathy of prematurity (ROP) that will require treatment in correlation with gestational age at birth (GA). STUDY DESIGN: In total, 2941 infants born <32 weeks GA were eligible from five cohorts of preterm infants previously collected for analysis in WINROP (Weight IGF-I Neonatal ROP) from the following locations: Sweden (EXPRESS) (n = 426), North America (n = 1772), Boston (n = 338), Lund (n = 52), and Gothenburg (n = 353). Data regarding GA at birth, birth weight (BW), gender, and need for ROP treatment were retrieved. Birth weight standard deviation scores (BWSDS) were calculated with Swedish as well as Canadian reference models. Small for gestational age (SGA) was defined as BWSDS less than -2.0 SDS using the Swedish reference and as BW below the 10th percentile using the Canadian reference charts. RESULTS: Univariate analysis showed that low GA (p<0.001), low BW (p<0.001), male gender (p<0.05), low BWSDSCanada (p<0.001), and SGACanada (p<0.01) were risk factors for ROP that will require treatment. In multivariable logistic regression analysis, low GA (p<0.0001), male gender (p<0.01 and p<0.05), and an interaction term of BWSDS*GA group (p<0.001), regardless of reference chart, were risk factors. Low BWSDS was less important as a risk factor in infants born at GA <26 weeks compared with infants born at GA ≥26 weeks calculated with both reference charts (BWSDSSweden, OR = 0.80 vs 0.56; and BWSDSCanada, OR = 0.72 vs 0.41). CONCLUSIONS: Low BWSDS as a risk factor for vision-threatening ROP is dependent on the infant's degree of immaturity. In more mature infants (GA ≥26 weeks), low BWSDS becomes a major risk factor for developing ROP that will require treatment. These results persist even when calculating BW deficit with different well-established approaches.

Neonatal IGF-1/IGFBP-1 axis and retinopathy of prematurity are associated with increased blood pressure in preterm children.

AIM: Preterm children are at risk of developing increased blood pressure (BP). We evaluated possible associations between BP, early insulin-like growth factor-1 (IGF-1) and IGF-binding protein-1 (IGFBP-1) levels and retinopathy of prematurity (ROP) in preterm children. METHODS: The study included 32 infants: median gestational age 28.1 weeks (range 24.6-31.3) and birthweight standard deviation scores (SDS) (±SD) 1.0 ± 2.7. IGF-1 and IGFBP-1 at postnatal weeks 32.6-34.6 and ROP stages were established after birth. BP was measured at the age of 4 years. The ratio (IGF-1)(2)/IGFBP-1 was created to investigate the influence of both IGF-1 and IGFBP-1 to later BP. RESULTS: Diastolic BP correlated with IGFBP-1, inversely correlated with IGF-1 and IGF-1(2)/IGFBP-1 (r = -0.71, p < 0.0001) and positively correlated with catch-up growth velocity from lowest weight SDS to age 36.5 weeks (r = 0.48, p < 0.01), independent of gestational age. Children with moderate-to-severe ROP as neonates had higher mean arterial BP [78 (±95%CI 74-83) vs 71 (±95%CI 68-75) mm Hg, p < 0.05] adjusted for gestational age and birthweight SDS compared to children diagnosed with no to mild ROP. CONCLUSION: Low neonatal IGF-1(2)/IGFBP-1 and severe ROP were associated with higher BP in 4-year-old children born very preterm and may thus predict future cardiovascular morbidity.

Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety.

BACKGROUND: In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP. METHODS: In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 µg/kg/24 h. RESULTS: Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded. CONCLUSION: In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.

Risk indicators for poor oral health in adolescents born extremely preterm.

Children born extremely preterm often suffer from medical complications that have been shown to affect their oral health as toddlers and school children.The aim of this study was to investigate oral health and possible risk indicators for poor oral health in adolescents born extremely preterm compared with a control group and relate the findings to medical diagnoses at the clinical examination. Also in the same groups, compare the frequency of mineralization disturbances and its relation to postnatal morbidity and treatments. The medical records postnatally,was noted in 45 extremely preterm infants with a gestational age (GA) of <29 weeks, at 12 - 16 years of age and in age and gender matched fullterm controls with 37-43 weeks GA. A dental clinical examination was performed including a salivary examination. Medical diagnoses were noted at the time of the survey. Data from the patient dental records at 3, 6, and 9 years of age was compiled. The findings were related to gestational age, birth weight, neonatal and postnatal medical diagnoses treatments and medical diagnoses at the clinical examination. The result showed that the prevalence of plaque, gingivitis and the occurrence of Streptococcus mutans were higher among adolescents born extremely preterm compared to matched controls, and the saliva secretion was lower in the extremely preterm infants. The frequency of caries did not differ between the groups. Mineralization disturbances were more frequent in the primary dentition and more severe in the permanent dentition among the children born extremely preterm. No association between dental pathology, neonatal and postnatal morbidity and treatments was found. In conclusion, adolescents born extremely preterm have an increased number of risk indicators for a poorer oral outcome compared with the controls and more severe mineralization disturbances. These findings may imply an increased vulnerability for poorer oral health later in life.