Adolescent growth: genes, hormones and the peer group. Proceedings of the 20th Aschauer Soiree, held at Glücksburg castle, Germany, 15th to 17th November 2013.

The association between poverty, malnutrition, illness and poor socioeconomic conditions on the one side, and poor growth and short adult stature on the other side, is well recognized. Yet, the simple assumption by implication that poor growth and short stature result from poor living conditions, should be questioned. Recent evidence on the impact of the social network on adolescent growth and adult height further challenges the traditional concept of growth being a mirror of health. Twenty-nine scientists met at Glücksburg castle, Northern Germany, November 15th - 17th 2013, to discuss genetic, endocrine, mathematical and psychological aspects and related issues, of child and adolescent growth and final height.

Reference chart of inspiratory muscle strength: a new tool to monitor the effect of pre-operative training.

OBJECTIVES: To develop a reference chart to monitor inspiratory muscle strength during pre-operative inspiratory muscle training for patients at high risk of developing postoperative pulmonary complications awaiting coronary artery bypass graft (CABG) surgery. DESIGN: Secondary data analysis using patients from the intervention arm of a randomised clinical trial. SETTING: University medical centre. PARTICIPANTS: Patients at high risk of developing postoperative pulmonary complications awaiting CABG surgery. INTERVENTIONS: Patients performed inspiratory muscle training seven times per week for at least 2 weeks before surgery. MAIN OUTCOME MEASURES: Maximal inspiratory muscle strength. RESULTS: A new reference chart was produced using a non-linear time trend model with a normal error structure. CONCLUSIONS: The chart is a novel tool for monitoring the progress of inspiratory muscle training for physiotherapy practice. Wider use of this chart is recommended.

Estimation of caries experience by multiple imputation and direct standardization.

Valid estimates of caries experience are needed to monitor oral population health. Obtaining such estimates in practice is often complicated by nonresponse and missing data. The goal of this study was to estimate caries experiences in a population of children aged 5 and 11 years, in the presence of nonresponse and missing data. Four estimation methods are compared. Each method makes implicit assumptions about the processes that caused the nonresponse and the missing data. Three of the four methods are based on unrealistic assumptions about the missing data and underestimate caries experience. Under the missing at random assumption, multiple imputation in combination with direct standardization corrects for the deficiencies of current methodology. In the presence of missing data and nonresponse, we recommend a combination of multiple imputation and direct standardization to obtain correct estimates of caries experience.

Personalized approach to growth hormone treatment: clinical use of growth prediction models.

The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.

Diversity in auxology: between theory and practice. Proceedings of the 18th Aschauer Soiree, 13th November 2010.

Auxology has developed from mere describing child and adolescent growth into a vivid and interdisciplinary research area encompassing human biologists, physicians, social scientists, economists and biostatisticians. The meeting illustrated the diversity in auxology, with the various social, medical, biological and biostatistical aspects in studies on child growth and development.

Body size and growth in 0- to 4-year-old children and the relation to body size in primary school age.

Excess weight in early life is believed to increase susceptibility to obesity, and in support of such theory, excess weight and fast weight gain in early childhood have been related to overweight later in life. The aim of this study was to review the literature on body size and growth in 0- to 4-year-old children and the association with body size at age 5-13 years. In total, 43 observational studies on body size and/or growth were included, of which 24 studies had been published in 2005 or later. Twenty-one studies considered body size at baseline, and 31 studies considered growth which all included assessment of weight gain. Eight (38%) studies on body size, and 15 (48%) on weight gain were evaluated as high-quality studies. Our results support conclusions in previous reviews of a positive association between body size and weight gain in early childhood, and subsequent body size. Body size at 5-6 months of age and later and weight gain at 0-2 years of age were consistently positively associated with high subsequent body size. Results in this review were mainly based on studies from developed Western countries, but seven studies from developing countries showed similar results to those from developed countries.

Growth variation, final height and secular trend. Proceedings of the 17th Aschauer Soiree, 7th November 2009.

Growth and body height have always been topics interesting to the public. In particular, the stupendous increase of some 15-19cm in final adult height during the last 150 years in most European countries (the "secular trend"), the concomitant changes in body and head proportions, the tendency towards early onset of sexual maturation, the changes in the age when final height is being reached, and the very recent trend in body mass index, have generated much scientific literature. The marked plasticity of growth in height and weight over time causes problems. Child growth references differ between nations, they tend to quickly become out of date, and raise a number of questions regarding fitting methods, effects caused by selective drop-out, etc. New findings contradict common beliefs about the primary importance of nutritional and health related factors for secular changes in growth. There appears to be a broad age span from mid-childhood to early adolescence that is characterised by a peculiar insusceptibility. Environmental factors that are known to influence growth during this age span appear to have only little or no impact on final height. Major re-arrangements in height occur at an age when puberty has almost been completed and final height has almost been reached, implying that factors, which drive the secular trend in height, are limited to early childhood and late adolescence.

Child-care use and the association with body mass index and overweight in children from 7 months to 2 years of age.

OBJECTIVES: Studies regarding the association of child-care use with body mass index (BMI), overweight or obesity development show contradictory results. This study examined the relationship between child-care use and BMI z-scores and overweight, as well as associates of child-care use in children up to 2 years old. METHODS: Longitudinal data originated from the Dutch KOALA Birth Cohort Study. Questionnaires assessed child-care use at ages 7 months and 1 and 2 years (N=2396). Height and weight assessed at 1 and 2 years were used to calculate BMI z-scores. Overweight was defined as a BMI z-score of ≥85th percentile. The influence of child-care use on weight development was tested using backward linear and logistic regression analyses. Outcomes were: (1) BMI z-score at 1 and 2 years; (2) change in BMI z-score between 1 and 2 years; (3) overweight vs non-overweight at 1 and 2 years; and (4) change from normal weight to overweight vs remaining normal weight between 1 and 2 years. The association between child-care use and parental background characteristics was tested using backward logistic regression analyses. RESULTS: Child-care use (no/yes) at 1 and 2 years positively predicted BMI z-scores at age 2 years, as well as change in BMI z-score between 1 and 2 years. These associations were adjusted for various covariates (for example, parental working hours). Furthermore, child-care use significantly increased the odds of being overweight at age 1 year. There were few differences in BMI or overweight between intensive (>16 h per week) and limited child-care use (≤16 h). Child-care use was positively associated with various parental characteristics, including parental working hours and maternal educational level. CONCLUSION: The findings suggest a small influence of child-care use on weight development in very young children. The child-care setting could have an important role in preventive interventions against overweight and obesity development in young children.

Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels.

BACKGROUND: Besides short stature, gonadal dysgenesis leading to a lack of oestrogen is one of the main characteristics of Turner syndrome (TS). In most TS girls, puberty is induced with exogenous oestrogens. OBJECTIVE: To describe the pubertal development and uterine dimensions achieved by low-dose 17beta-oestradiol (17beta-E2) orally started at an appropriate age. Additionally, to determine whether serum hormone levels aid evaluation of pubertal progression. DESIGN: In 56 TS girls, we prospectively studied pubertal stage, serum E2, LH, FSH, SHBG and oestrone (E1), starting oestrogen treatment with a low-dose 17beta-E2 (5 microg/kg/day) during GH treatment at mean (SD) age 12.7 (0.7) years. Hormone levels were measured at start, 3 months after start and after increasing 17beta-E2 dosage. Uterine dimensions were measured in 39 TS women at age 19.9 (2.2) years. RESULTS: Although breast and pubic hair development were similar to that in normal Dutch girls up to Tanner stage B5 and P5, respectively, breast development was 2 years later. Before oestrogen therapy, E2 levels were comparable to those in prepubertal girls. With a 17beta-E2 dose of 5 microg/kg/day, these levels increased significantly, becoming comparable to normal late pubertal or adult concentrations, whereas SHBG levels were unchanged. At the adult 17beta-E2 dose, SHBG had increased significantly. Uterus shape was juvenile in four (10.2%), cylindrical in four and mature-adult shaped in 31 (79.5%) of TS patients. CONCLUSIONS: During GH treatment in TS girls, normal breast development up to B5 can be mimicked, with just a 2-year delay. In a clinical setting, serum hormone levels provide no additional information for evaluating pubertal progression. After age-appropriate pubertal induction, uterine dimensions in women aged nearly 20 years were subnormal. It remains unclear whether this was related to E2 dosage, timing or duration, or factors related to TS.

Intelligence of very preterm or very low birthweight infants in young adulthood.

OBJECTIVE: To examine the effect of intrauterine and neonatal growth, prematurity and personal and environmental risk factors on intelligence in adulthood in survivors of the early neonatal intensive care era. METHODS: A large geographically based cohort comprised 94% of all babies born alive in the Netherlands in 1983 with a gestational age below 32 weeks and/or a birth weight >1500 g (POPS study). Intelligence was assessed in 596 participants at 19 years of age. Intrauterine and neonatal growth were assessed at birth and 3 months of corrected age. Environmental and personal risk factors were maternal age, education of the parent, sex and origin. RESULTS: The mean (SD) IQ of the cohort was 97.8 (15.6). In multiple regression analysis, participants with highly educated parents had a 14.2-point higher IQ than those with less well-educated parents. A 1 SD increase in birth weight was associated with a 2.6-point higher IQ, and a 1-week increase in gestational age was associated with a 1.3-point higher IQ. Participants born to young mothers (<25 years) had a 2.7-point lower IQ, and men had a 2.1-point higher IQ than women. The effect on intelligence after early (symmetric) intrauterine growth retardation was more pronounced than after later (asymmetric) intrauterine or neonatal growth retardation. These differences in mean IQ remained when participants with overt handicaps were excluded. CONCLUSIONS: Prematurity as well as the timing of growth retardation are important for later intelligence. Parental education, however, best predicted later intelligence in very preterm or very low birthweight infants.

Selective association of multiple sclerosis with infectious mononucleosis.

Previous studies have suggested an association between multiple sclerosis (MS) and infectious mononucleosis (IM) but data on the exact strength of this association or its selectivity have been conflicting. In this study we have evaluated the association between MS and a variety of common childhood infections and afflictions in a large population-based case-control study involving 2,877 MS cases and 2,673 controls in the Netherlands. We examined the frequency of different common infections and afflictions before the age of 25 and the age at which they occurred, using a self-administered questionnaire. The Odds ratios (ORs) for the occurrence of a variety of clinically manifest common childhood infections including rubella, measles, chicken pox and mumps before the age of 25 for MS cases versus controls ranged between 1.14 and 1.42, values similar to those for irrelevant probe variables used to reveal recall bias. In contrast, the OR for clinically manifest IM in MS cases versus controls, corrected for demographic variables, was 2.22 (95% confidence interval 1.73 - 2.86; P < 0.001). The average age of onset of IM in the population of MS cases (16.5 years) did not differ from controls (16.8 years). Our data confirm previous much smaller studies to show that the risk for MS is significantly enhanced by prior IM, and extend those previous data by showing that this association is far stronger than with other common childhood infections or afflictions.

Developing evidence-based guidelines for referral for short stature.

OBJECTIVE: To establish evidence-based guidelines for growth monitoring on a population basis. STUDY DESIGN: Several auxological referral criteria were formulated and applied to longitudinal growth data from four different patient groups, as well as three samples from the general population. RESULTS: Almost 30% of pathology can be detected by height standard deviation score (HSDS) below -3 or at least two observations of HSDS below -2.5 at a low false-positive rate (<1%) in 0-3-year-old infants. For 3-10-year olds, a rule concerning distance to target height of >2 SD in combination with HSDS <-2.0 has the best predictive value. In combination with a rule on severe short stature (<-2.5 SDS) and a minor contribution from a rule on "height deflection", 85.7% of children with Turner syndrome and 76.5% of children who are short because of various disorders are detected at a false-positive rate of 1.5-2%. CONCLUSIONS: The proposed guidelines for growth monitoring show high sensitivity at an acceptably low false-positive rate in 3-10-year-old children. Distance to target height is the most important criterion. Below the age of 3 years, the sensitivity is considerably lower. The resulting algorithm appears to be suitable for industrialised countries, but requires further testing in other populations.

Construction of the World Health Organization child growth standards: selection of methods for attained growth curves.

The World Health Organization (WHO), in collaboration with a number of research institutions worldwide, is developing new child growth standards. As part of a broad consultative process for selecting the best statistical methods, WHO convened a group of statisticians and child growth experts to review available methods, develop a strategy for assessing their strengths and weaknesses, and discuss methodological issues likely to be faced in the process of constructing the new growth curves. To select the method(s) to be used, the group proposed a two-stage decision-making process. First, to select a few relevant methods based on a list of set criteria and, second, to compare the methods using available tests or other established procedures. The group reviewed 30 methods for attained growth curves. Using the pre-defined criteria, a few were selected combining five distributions and two smoothing techniques. Because the number of selected methods was considered too large to be fully tested, a preliminary study was recommended to evaluate goodness of fit of the five distributions. Methods based on distributions with poor performance will be eliminated and the remaining methods fully tested and compared.

Anthropometry of Malawian live births between 35 and 41 weeks of gestation.

The aim of this analysis was to construct cross-sectional gestational age specific percentile curves for birthweight, length, head and mid-arm circumference for Malawian babies, and to compare these percentiles with reference values for babies born to women with normal pregnancies, from a developed country. A cross-sectional study which enrolled pregnant women attending two study hospitals between March 1993 and July 1994 was undertaken. Data on maternal socio-economic status, newborn anthropometry, previous obstetric history and current pregnancy were collected. Smoothed percentile values were derived using the LMS method. Malawian reference percentiles were constructed for fetal growth from 35 weeks' gestation for singleton births. Mean birthweight, length and head circumference were lower at all gestational ages for Malawian compared with Swedish newborns. Fetal growth per completed gestational week was higher by 60 g in weight, 0.5 cm in length and 0.2 cm in head circumference in Swedish compared with Malawian babies. Growth restriction was present from 35 to 41 weeks' gestation. The pattern for the 10th percentile suggested that this was occurring from well before 35 weeks' gestation in a proportion of babies.

Catch-up growth in Malawian babies, a longitudinal study of normal and low birthweight babies born in a malarious endemic area.

INTRODUCTION: Infant growth has not been studied in developing countries in relation to maternal factors related to malaria in pregnancy and maternal illiteracy. OBJECTIVE: To describe growth patterns in infants with low and normal birthweight and determine maternal risk factors for infant undernutrition. METHODS: Babies born in a rural district of southern Malawi were recruited. An infant cohort was selected on the basis of low or normal birthweight. Weight and length were recorded at birth and at 4-weekly intervals until at 52 weeks after birth. Maternal characteristics at first antenatal attendance and delivery were obtained. Odds ratios in univariate analysis were adjusted for birthweight. Factors included in the multivariate regression included maternal illiteracy, season of birth, maternal iron deficiency and number of infant illness episodes. RESULTS: Low birthweight infants were shorter and lighter throughout infancy than either normal birthweight or international reference values. At 12 months, placental or peripheral malaria at delivery (adjusted odds 1.8; 1.0, 3.1), number of infant illness episodes (AOR = 2.1; 1.2, 3.6) and maternal illiteracy (AOR = 2.7; 1.5, 4.9) were independently associated with low weight for age. Maternal short stature (AOR = 1.8; 1.1. 3.2), male sex (AOR = 2.4; 1.4, 4.1), number of infant illness episodes (AOR = 2.6; 1.5, 4.4), and birth in the rainy season (2.1; 1.2, 3.7) were independently associated with stunting. Placental or peripheral malaria at delivery (AOR = 2.2; 1.1, 4.4) and number of illness episodes (AOR = 2.2; 1.1, 4.5) were independently associated with thinness. CONCLUSION: Malaria during pregnancy and maternal illiteracy are important maternal characteristics associated with infant undernutrition. Innovative health/literacy strategies are required to address malaria control in pregnancy in order to reduce the magnitude of its effects on infant undernutrition.

Individual growth curve models for assessing evidence-based referral criteria in growth monitoring.

The goal of this study is to assess whether a growth curve model approach will lead to a more precise detection of Turner sydnrome (TS) than conventional referral criteria for growth monitoring. The Jenss-Bayley growth curve model was used to describe the process of growth over time. A new screening rule is defined on the parameters of this growth curve model, parental height and gestational age. The rule is applied to longitudinal growth data of a group of children with TS (n=777) and a reference (n=487) group. The outcome measures are sensitivity, specificity and median referral age. Growth curve parameters for TS children were different from reference children and can therefore be used for screening. The Jenss-Bayley growth model, which uses all longitudinal measurements from birth to a maximum age of 5 years with at least one measurement after the age of 2, together with parental height and gestational age can achieve a sensitivity of 85.2 per cent with a specificity of 99.5 per cent and a median referral age of 4.2 (the last measurement between the age of 2 and 5 of each child is considered to be the moment of referral). Sensitivity increases by 2 percentage points when decreasing the specificity to 99 per cent. The Jenss-Bayley growth model from birth to a maximum age of 8 years with at least one measurement after the age of 2, together with parental height results in a sensitivity of 89.0 per cent with a specificity of 99.5 per cent and a median referral age of 6.1. For a specificity of 98 per cent, we obtain a sensitivity of 92.3 per cent. In comparison to conventional rules applied to the same data, sensitivity is about 11-30 percentage points higher at the same level of specificity for the Jenss-Bayley growth rule. We conclude that from the age of 4, growth curve models can improve the screening on TS to conventional screening rules.

Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders.

AIMS: To obtain age references for sitting height (SH), leg length (LL), and SH/H ratio in the Netherlands; to evaluate how SH standard deviation score (SDS), LL SDS, SH/H SDS, and SH/LL SDS are related to height SDS; and to study the usefulness of height corrected SH/H cut-off lines to detect Marfan syndrome and hypochondroplasia. METHODS: Cross-sectional data on height and sitting height were collected from 14,500 children of Dutch origin in the age range 0-21 years. Reference SD charts were constructed by the LMS method. Correlations were analysed in three age groups. SH/H data from patients with Marfan syndrome and genetically confirmed hypochondroplasia were compared with height corrected SH/H references. RESULTS: A positive association was observed between H SDS, SH SDS, and LL SDS in all age groups. There was a negative correlation between SH/H SDS and height SDS. In short children with a height SDS <-2 SDS, a cut-off limit of +2.5 SD leads to a more acceptable percentage of false positive results. In exceptionally tall children, a cut-off limit of -2.2 SDS can be used. Alternatively, a nomogram of SH/H SDS versus H SDS can be helpful. The sensitivity of the height corrected cut-off lines for hypochondroplasia was 80% and for Marfan syndrome only 30%. CONCLUSIONS: In exceptionally short or tall children, the dependency of the SH/H ratio (SDS) on height SDS has to be taken into consideration in the evaluation of body proportions. The sensitivity of the cut-off lines for hypochondroplasia is fair.

Anthropometry of fetal growth in rural Malawi in relation to maternal malaria and HIV status.

OBJECTIVE: To describe fetal growth centiles in relation to maternal malaria and HIV status, using cross sectional measurements at birth. DESIGN: A cross sectional study of pregnant women and their babies. Data on maternal socioeconomic status and current pregnancy, including HIV status and newborn anthropometry, were collected. Malaria parasitaemia was assessed in maternal peripheral and placental blood, fetal haemoglobin was measured in cord blood, and maternal HIV status was determined. SETTING: Two district hospitals in rural southern Malawi, between March 1993 and July 1994. OUTCOME VARIABLES: Newborn weight, length, Rohrer's ponderal index. RESULTS: Maternal HIV (adjusted odds ratio (AOR) 1.76 (95% confidence interval 1.04 to 2.98)) and first pregnancy (AOR 1.83 (1.10 to 3.05)) were independently associated with low weight for age. Placental or peripheral parasitaemia at delivery (AOR 1.73 (1.02 to 2.88)) and primigravidae (AOR 2.13 (1.27 to 3.59)) were independently associated with low length for age. Maternal malaria at delivery and primiparity were associated with reduced newborn weight and length but not with disproportionate growth. Maternal HIV infection was associated only with reduced birth weight. The malaria and parity effect occurred throughout gestational weeks 30-40, but the HIV effect primarily after 38 weeks gestation. CONCLUSION: Fetal growth retardation in weight and length commonly occurs in this highly malarious area and is present from 30 weeks gestation. A maternal HIV effect on fetal weight occurred after 38 weeks gestation.