because more immature neonates are surviving , the incidence of bronchopulmonary dysplasia ( bpd ) has not decreased .
bpd impairs early growth , and prematurity is associated with altered eating habits in later life .
inflammation , a key pathogenic factor of bpd , affects metabolism , nutritional requirements , and growth in the neonatal period , but its association with later growth is less clear .
preterm infants have lower adiponectin levels compared with term children at term - equivalent age .
growth and nutrition may affect adipokine levels . whether the growth and nutrition of the school - aged survivors of very low birth weight ( vlbw ; birth weight < 1500 g ) and bpd affect their adipokine status is not known .
our aim was to study nutritional intake and growth , with respect to plasma levels of adipokines and neonatal factors , in vlbw school children with and without severe radiographic bpd and term controls .
our hypotheses were that ( 1 ) bpd children and vlbw controls would present with similar growth parameters , but term children would demonstrate better growth than vlbw cases ; ( 2 ) nutritional differences would exist between bpd children and controls ; and ( 3 ) plasma adipokine concentrations would be associated with growth parameters in vlbw children at school age .
tampere university hospital records were searched to find vlbw children born between january 1 , 1995 , and april 13 , 2003 , with severe , northway grade iii to iv cystic radiographic bpd and age - matched controls without radiographic bpd .
we examined 59 children 6 to 14 years of age , comprising 21 vlbw children with radiographic bpd , 19 vlbw children without radiographic bpd , and 19 children born at term .
the median age of the study cohort was 11.3 years ( range = 6.3 - 14.2 ) , and 64% were boys .
the age and sex profile of the 3 groups was similar , with the exception of a lower - than - average percentage of boys in the vlbw control group ( 58% ) .
parents were considered to be overweight if their body mass index ( bmi ) was more than 25 kg / m .
the children were examined by a pediatrician ( tk ) who measured their height , weight , and head circumference , and their bmi standard deviation score ( bmi - sds ) was determined according to finnish age - specific and sex - specific references .
microcephaly was defined as a head circumference of less than 2sd and macrocephaly as a head circumference of more than + 2sd .
overweight and underweight were defined as bmi - sds of more than 1.16 and less than 1.65 in girls and more than 0.78 and less than 1.83 in boys .
long - term illnesses , such as asthma , cerebral palsy , epilepsy , and short bowel syndrome , were recorded .
thigh , hip , waist , and middle upper - arm circumferences were measured with a tape measure , and the mean of 2 measurements was recorded .
biceps , triceps , subscapular , and suprailiacal skinfold thicknesses were measured with a harpenden skinfold caliper according to the guidelines of the manufacturer ( baty international , west sussex , uk ) , and the mean of 3 measurements was recorded .
the adiponectin , adipsin , resistin , and leptin levels in plasma were determined as previously described ; adipokine concentrations did not differ between the groups , as reported earlier .
the parents completed a food record of everything the participants ate and drank over 3 consecutive days , and a trained nutritionist interviewed the families and calculated nutrient intakes with the diet32 dietary analysis program ( aivo ab sverige , solna , sweden ) .
the nutritional intakes were compared with national age - specific recommendations and the upper level of tolerable intake for adults .
an energy intake that was up to 200 kcal above or below the age- and sex - adjusted estimated energy requirement was considered normal to cover different levels of physical activity .
the ethics committee of the hospital district approved the study protocol , and written , informed consent was obtained from the parents .
spss statistics for windows , version 18.0 ( spss inc , chicago , il ) , was used for the statistical analyses .
independent - sample t - tests or 1-way analysis of variance were used for normally distributed variables , the mann - whitney u test or kruskal - wallis test for non - gaussian variables , and the  test or fisher s exact test for categorical variables . values of p < .05 were considered statistically significant . in vlbw children ,
the correlations between adipokine concentrations , anthropometric parameters , and nutrient intake were studied using pearson s r correlation test for normally distributed variables and spearman s rank correlation coefficient (  ) test for nonnormally distributed variables . logistic regression analysis was carried out among vlbw children to examine predictors for the lowest and highest quartiles of bmi - sds and the lowest quartile of length for age and microcephaly .
the first variables were birth weight , neonatal sepsis , radiographic bpd , severe intraventricular hemorrhage ( ivh ) of grade iii or more , or periventricular leukomalacia and bell stage 2 or 3 necrotizing enterocolitis ( nec ) .
the second variables were the intake of energy , fat , protein , and carbohydrates .
spss statistics for windows , version 18.0 ( spss inc , chicago , il ) , was used for the statistical analyses .
independent - sample t - tests or 1-way analysis of variance were used for normally distributed variables , the mann - whitney u test or kruskal - wallis test for non - gaussian variables , and the  test or fisher s exact test for categorical variables .
values of p < .05 were considered statistically significant . in vlbw children , the correlations between adipokine concentrations , anthropometric parameters , and nutrient intake were studied using pearson s r correlation test for normally distributed variables and spearman s rank correlation coefficient (  ) test for nonnormally distributed variables . logistic regression analysis was carried out among vlbw children to examine predictors for the lowest and highest quartiles of bmi - sds and the lowest quartile of length for age and microcephaly .
the first variables were birth weight , neonatal sepsis , radiographic bpd , severe intraventricular hemorrhage ( ivh ) of grade iii or more , or periventricular leukomalacia and bell stage 2 or 3 necrotizing enterocolitis ( nec ) .
the second variables were the intake of energy , fat , protein , and carbohydrates .
one child with radiographic bpd with a birth weight of less than 2sd was considered small for gestational age . children with radiographic bpd had poorer initial weight gain and higher rates of ivh , sepsis , and nec than the vlbw controls ( table 1 ) .
three children with radiographic bpd with nec had undergone bowel resection , and 1 had short bowel syndrome .
abbreviations : vlbw , very low birth weight ; bpd , bronchopulmonary dysplasia ; ivh , intraventricular hemorrhage .
n = 18 in the bpd group and n = 12 in the control group .
at school age , the only anthropometric difference between the groups was in head circumference ( table 2 ) .
children with radiographic bpd had a smaller age - adjusted head circumference and were more likely to have microcephaly than the controls ( table 2 ) .
in all , 8 vlbw children with microcephaly at school age had smaller age - adjusted head circumferences at birth , with a mean and sd of 0.5 ( 0.86 ) versus 0.39 ( 0.62 ) , and their weight gain during initial hospitalization was poorer , with a median ( range ) of 14.8 g / d ( 14.3 to 20.4 ) versus 22.8 g / d ( 7.0 to 28.5 ) , compared with vlbw children without microcephaly .
the bmi - sds and the height for age were similar in vlbw children with and without microcephaly .
growth statistics of the school - aged children . abbreviations : bpd , bronchopulmonary dysplasia ; vlbw , very low birth weight ; bmi - sds , body mass index standard deviation score ; hc , head circumference ; muac , middle - upper - arm circumference ; sft , skinfold thickness .
nec survivors had a smaller head circumference at school age than children without nec , with a mean ( sd ) of 1.6 ( 2.8 ) versus 0.4 ( 1.3 ) , but the other anthropometric parameters did not differ .
one of the 5 children with severe ivh or periventricular leukomalacia and 2 of the 4 children with cerebral palsy had microcephaly at school age .
in addition , 9 of the radiographic bpd and 4 of the vlbw control children with long - term illnesses had smaller waist - to - hip ratios compared with children without those conditions .
plasma adipokine concentrations were similar in prepubertal and pubertal children , with girls having higher adipsin levels than boys , with a median ( range ) of 916 ng / ml ( 598 - 1264 ) versus 787 ng / ml ( 483 - 1409 ) .
the girls leptin levels were also higher , at 7.1 ng / ml ( 2.1 - 37.6 ) versus 1.8 ng / ml ( 0.5 - 50.0 ) , than those of the boys , but the adiponectin and resistin levels were similar between the sexes .
food records were not returned by the parents of 1 child with radiological bpd , 3 vlbw controls , and 1 term child .
there were no differences between the groups in regard to nutritional intake ( table 3 ) , but daily nutritional intake recommendations were poorly met ( table 4 ) , with the exception of vitamin b12 and phosphate , which were adequate in all children .
abbreviations : bpd , bronchopulmonary dysplasia ; vlbw , very low birth weight ; sfa , saturated fatty acids ; e% , percentage of total energy intake ; mufa , monounsaturated fatty acids ; pufa , polyunsaturated fatty acids ; -te , -tocopherol equivalent , equals 1 mg -tocopherol ; vitamin a retinol equivalent , 1 g retinol , equals 12 g -carotene ; niacin equivalent , 1 mg niacin , equals 60 mg tryptophan .
abbreviations : rdi , recommended daily intake ; bpd , bronchopulmonary dysplasia ; vlbw , very low birth weight ; sfa , saturated fatty acids ; mufa , monounsaturated fatty acids ; pufa , polyunsaturated fatty acids ; cho , carbohydrates . 
plasma leptin concentrations correlated positively with bmi - sds (  = 0.57 ) and negatively with fat intake (  = 0.36 ) .
adiponectin (  = 0.36 ) , adipsin ( r = 0.33 ) , and leptin (  = 0.55 ) levels correlated negatively with energy intake , as did resistin levels with carbohydrate intake (  = 0.36 ) . birth length for gestational age correlated negatively with resistin levels (  = 0.32 ) and birth head circumference for gestational age with adiponectin levels at school age (  = 0.47 ) . in the univariate logistic regression analysis ,
radiographic bpd was associated with an increased risk of microcephaly , with an or of 9.69 ( 95% ci = 1.06 - 88.65 ) , and so was neonatal sepsis ( or = 11.25 ; 95% ci = 1.91 - 66.39 ) .
in addition , neonatal sepsis seemed to predict short stature at school age in the multivariate analysis ( or = 11.57 ; 95% ci = 1.01 - 132.40 ) . when gestational age was entered into the multivariate model instead of birth weight , the association between neonatal sepsis and short stature was no longer significant .
neonatal dexamethasone treatment was associated with microcephaly at school age in the univariate analysis ( or = 8.63 ; 95% ci = 1.44 - 51.72 ) but not when entered into the multivariate analysis .
short stature was found to be negatively associated with the intake of protein ( or = 0.35 ; 95% ci = 0.14 - 0.85 ) , fat ( or = 0.12 ; 95% ci = 0.02 - 0.79 ) , and carbohydrates ( or = 0.37 ; 95% ci = 0.15 - 0.37 ) and positively associated with energy intake ( or = 1.38 ; 95% ci = 1.03 - 1.58 ) .
school - aged vlbw survivors with radiographic bpd had smaller head circumferences and were more likely to have microcephaly than vlbw and term controls , but no other differences were found in growth parameters or nutritional intake .
bmi - sds correlated with leptin levels , but no other associations between plasma adipokine concentrations and anthropometric parameters at school age were found .
there were negative correlations between leptin concentrations and fat intake , resistin levels and carbohydrate intake , and adiponectin , adipsin , and leptin concentrations and energy intake .
school - aged vlbw children have been reported to have smaller head circumferences and higher levels of microcephaly than term controls .
bpd has been associated with small head circumference at school age , but not in all studies . because bpd mainly affects the most immature infants , neonatal comorbidity is high , and the independent effect of bpd on growth is difficult to establish .
in contrast , our children with microcephaly had poorer neonatal weight gain compared with the other vlbw children
. children with microcephaly at school age were the sickest infants and had nec , sepsis , and pulmonary problems requiring steroid treatment .
the head circumference measurements between the birth and the study date were not available in our study , which is a weakness . although children with microcephaly at school age had smaller age - adjusted birth head circumference than vlbw children without microcephaly , none had microcephaly at birth .
a previous study estimates that the critical period of brain growth extends to late infancy , and after the first year of life , the small head circumference tends to persist .
parental head circumference was not measured , which is a major limitation , because the hereditability of head circumference has been reported to be up to 88% in childhood .
although most of the children reported a lower - than - recommended daily energy intake , only 4 were underweight .
however , the amount of physical exercise was not recorded , and this may explain the adequate weight gain .
all children reported an excessive intake of saturated fatty acids , whereas low intakes of fiber and micronutrients were common .
similar unfavorable dietary habits have been reported in young vlbw adults , and because this increases the risk of later chronic diseases , counseling about healthier eating from childhood could be an important tool for preventing disease . recommended micronutrient intakes are set to the average requirement of + 2sd , and therefore , a lower - than - recommended intake does not mean that there was an inadequate food supply .
our food diaries can be regarded as reliable because they were checked with the nutritionist , but the food diaries only provide an estimate of short - term intake , with variability depending on the season and different food - related occasions .
the only correlation between plasma adipokine levels and growth parameters in school - aged vlbw survivors was between bmi - sds and leptin levels .
greater weight has previously been associated with higher leptin and lower adiponectin levels in children .
it seems that the association between inflammatory marker levels and growth is not more marked in vlbw survivors than in other school children .
lower leptin levels were correlated with a greater intake of energy and fats . in a previous study of obese adults , weight correlated positively with leptin and negatively with leptin receptor concentrations , and both leptin and leptin receptor levels correlated negatively with total energy intake .
that study highlighted the role of the leptin / leptin receptor levels in satiety control and total energy intake and the importance of the synergistic interrelationships between the adipokines .
adiponectin has been linked to insulin sensitization , and adipsin to triglyceride storage , and a decrease in energy intake has been associated with an increase in adiponectin levels in adults .
levels of resistin , which have a controversial effect on glucose metabolism , have been shown to correlate negatively with carbohydrate intake .
in addition , a high - fiber diet has been shown to decrease resistin levels in children .
it seems that adipokine concentrations , and thus the risk of metabolic diseases , can be modified by a diet .
nec survivors had a smaller head circumference than children who had not had nec , and neonatal sepsis was associated with microcephaly and shorter stature at school age . neonatal sepsis and nec
have been shown to increase the risk of growth impairment in toddlers , and the resulting systemic inflammatory response has been shown to activate a local inflammatory response in the brain , leading to impaired neurodevelopment and head growth .
our results suggest that the impact of neonatal inflammation on growth , together with neurocognitive development as a result of microcephaly , may persist up to school age .
head circumference at birth correlated negatively with adiponectin levels in vlbw children , as did birth length with resistin levels .
previous studies have found an association between low birth weight and low adiponectin levels at school age and high leptin levels in adults .
weight gain during infancy has been positively associated with leptin concentrations at school age and negatively associated with adiponectin levels at 17 years of age .
previous data on the growth of modern age bpd survivors at school age have been relatively limited .
our study is a single - center study that minimized the effect of different neonatal treatment protocols on the results but was also limited by the number of patients that were available .
the number of cases was not based on power analysis ; instead , all available patients with severe radiographic bpd treated in our hospital during an 8-year period were studied .
based on small groups and wide 95% cis , underpowering may be one reason for negative results . in the case of positive results , such as
the statistically significant trend of more instances of microcephaly in bpd children , the power is sufficient , although the number of cases is small .
children with radiographic bpd presented with poorer head growth and a greater incidence of microcephaly at school age than vlbw and term controls .
bmi - sds correlated with leptin levels , but otherwise , adipokine levels at school age seemed to have no association with growth parameters in vlbw children .
plasma adipokine levels correlated with nutritional intake , and as a result , dietary counseling would be beneficial .
ps : contributed to acquisition , analysis , and interpretation ; drafted the manuscript ; agrees to be accountable for all aspects of work ensuring integrity and accuracy .
pk : contributed to conception , design , analysis , and interpretation ; drafted the manuscript ; gave final approval .
tl : contributed to conception , design and analysis ; gave final approval . ot : contributed to conception , design , analysis , and interpretation ; drafted the manuscript ; gave final approval .
 this study evaluated nutrition and growth in relation to plasma adipokine levels in 21 very - low - birth - weight ( vlbw ) children with radiographic bronchopulmonary dysplasia ( bpd ) , 19 vlbw controls , and 19 term controls with a median age of 11.3 years . 
 we took anthropometric measurements ; assessed plasma levels of adipsin , resistin , adiponectin , and leptin ; and analyzed the children s 3-day food records . 
 children with bpd had a smaller age - adjusted head circumference and more microcephaly but no other significant growth differences . 
 daily recommended nutritional intake levels were poorly met but did not differ between the groups . 
 leptin levels correlated positively with the body mass index standard deviation score in vlbw children . 
 no other associations between adipokine concentrations and growth were found . there were negative correlations between leptin concentrations and fat intake , resistin levels and carbohydrate intake , and adiponectin , adipsin , and leptin levels and energy intake . 