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DOI 10.1007/s00467-010-1646-3
ORIGINAL ARTICLE
Received: 20 January 2010 / Revised: 17 June 2010 / Accepted: 26 July 2010 / Published online: 2 October 2010
# IPNA 2010
Abstract The aim of this study was to investigate the AGA children was similar. Renal functions were normal and
relationship between birth weight and blood pressure (BP) by similar in both groups. Three children (2 SGA, 1 AGA) with
means of ambulatory BP monitoring (ABPM) and renal normal glomerular filtration rate had higher microalbumin
functions in non-obese children who were born small-for- excretion and one SGA child had systolic hypertension
gestational age (SGA) at term. The study group consisted of according to the office BP. Our findings demonstrate that the
39 (19 female, 20 male; mean age 8.8±2.6 years) children influence of intrauterine growth restriction on BP is not
born SGA. Their data were compared to those of 27 (13 female, manifested during the childhood period, and they do not
14 male; mean age 8.2±2.9 years) children born appropriate- support the existence of a negative relationship between birth
for-gestational age (AGA). No difference between SGA and weight and BP in children.
AGA children was observed based on office BP measurements
and daytime, nighttime and 24-h ABPM. Seventeen SGA Keywords Small-for-gestational age (SGA) .
(48.6%) and nine AGA (37.5%) children had a 24-h systolic Ambulatory blood pressure monitoring . Hypertension .
BP (SBP) load over 25%, and seven of these (5 SGA, 2 AGA) Children . Microalbumin . Beta-2 microglobulin .
were hypertensive according to mean SBP values. The Beta-N-acetyl-D-glucosaminidase
prevalence of the non-dipping phenomenon in SGA and
in humans. Intrauterine growth restriction may also be Family history with regard to hypertension and kidney
responsible for the prenatal programming of BP. A number disease was recorded. In no cases was there a history or
of studies have shown an association between low birth family history that suggested renal disease.
weight and higher BP in later life [4–6], but others did not Following a thorough physical examination, anthropometric
provide support for fetal origin hypothesis as applied to BP measurements, including height and weight, were taken by
regulation, reporting that the association between birth size standard methods using the Harpenden stadiometer. The BMI
and later blood pressure was not significant [7–9]. was calculated as weight (kg)/height (m)2. Values of height and
Ambulatory blood pressure monitoring (ABPM) has been weight [15], BMI [16] and birth weight and length [17] were
increasingly used to investigate hypertension in different expressed as the standard deviation score (SDS). Δ height
pediatric populations. However, there are only a few reports SDS was defined as the difference (Δ) between birth length
on ABPM, microalbuminuria and renal functions in SGA SDS and current height SDS, and Δ weight SDS as the
children [10–13], and the utility of BP in SGA children has difference (Δ) between birth weight and current weight SDS.
not been well established. Therefore, the aim of this study was Target height (TH) was calculated from parental height
to investigate the relationship between birth weight and BP [father’s height (cm) + mother’s height (cm)]/2 − 6.5 cm
parameters by applying ABPM and evaluating microalbumi- (girls), + 6.5 cm (boys). Birth data and the measurements of
nuria and renal functions in a group of non-obese children the children at investigation are shown in Table 1.
born SGA and comparing their data to those of control
children born appropriate-for-gestational age (AGA). BP measurements
Table 1 Anthropometric parameters of the SGA and AGA children at birth and at the time of the study
parison of the data obtained on our study population with expressed as the arithmetic mean ± SD. Comparisons were
those of the general pediatric population using a published performed between the groups using parametric tests as
formula for office BP and ABPM [18, 19]. appropriate. The chi-square test was applied for the compar-
Renal functions were evaluated in all children. Urinary ison of prevalence between groups. Pearson's correlation test
proteins used as markers of glomerular damage due to was used to analyze BPs in relation to anthropometric
hyperfiltration and of tubular damage were analyzed. After variables. In the multiple regression analysis, office and
an overnight fast, serum samples were drawn for serum ambulatory BP SDS values and renal function tests were
urea and creatinine (Cr). Early morning urine was collected taken as dependent variables in separate models, and birth
from the children of both the SGA and AGA groups, and size, gender, age, Δ height SDS, Δ weight SDS and recent
the samples were kept at −20°C until analyzed for micro- BMI SDS were taken as independent variables and tested in
albumin, urinary beta-2 microglobulin (U-B2M), urinary each of these models. In the logistic regression analysis, we
beta-N-acetyl-D-glucosaminidase (UNAG) and urinary Cr. also used birth weight to predict the prevalence of
All patients had a normal renal function defined as a hypertension, BP loads and the non-dipper in unadjusted
glomerular filtration rate (GFR) of >90 ml/min/1.73 m2 (as models; in the multivariable logistic analysis, we included
determined by the Schwartz formula) [20]. age, gender, Δ weight SDS, Δ height SDS and BMI SDS as
independent variables. Significance was set for p<0.05.
Methods
Ethics statement
The serum Cr level was determined by the Jaffe method
(COBAS INTEGRA 800; Roche, Branchburg, NJ). Urine This study was approved by the local ethical committee.
creatinine and UNAG measurements were performed by the Informed consent was obtained from the parent(s) of both
colorimetric method (COBAS INTEGRA 800; Roche). Urine the cases and the controls.
albumin and U-B2M were measured by nephelometry using a
Behring BN ProSpec analyzer (Dade Behring, Milton Keynes,
UK). Microalbumin, UNAG and U-B2M levels were Results
expressed as a ratio to the urine Cr concentration.
Anthropometry
Statistical analysis
The anthropometric parameters of the SGA and AGA
All data were stored and analyzed using the SPSS 12 children at birth and at the time of the study are given in
statistical package (SPSS, Chicago, USA). Values are Table 1. The mean gestational age, mean age at the time of
122 Pediatr Nephrol (2011) 26:119–126
the study, sex and family history for hypertension of the time was shorter than 22 h due to device discomfort. The
children of both groups were not different. By definition, mean of ABPM records was 52 (range 22–76).
birth weight, length and SDS’s were significantly lower in The mean heart rates did not differ significantly between
SGA children than in AGA children (p<0.001). At the time the children in the SGA and AGA groups at any time point. In
of the investigation, weight SDS and BMI SDS fell within addition, there were no differences in office, the 24-h, daytime
normal limits and were similar in both groups. Although and nighttime SBP and DBP between the groups (Table 2).
SGA children were shorter than AGA children (p=0.01), The frequencies of systolic and/or diastolic hypertension in
their height SDS corrected for their parents was within the children of the SGA and AGA groups according to daytime,
normal limits (0.4±0.2). Δ height SDS and Δ weight SDS nighttime and 24 h ABPM were similar and did not show
were 1.1±0.9 and 1.8±0.9 in the SGA group and −0.1±0.8 significant differences based on these parameters (Table 3).
and −0.2±0.7 in the AGA group, respectively. The mean day to night fall (dipping) in SBP and DBP
was similar in both groups (14.04±5.8% and 12.8±7.8 for
BP parameters of SGA and AGA children SBP and 16.7±7.3% and 14.2±7.9% for DBP in SGA and
AGA children, respectively). The prevalence of the non-
There was no gender difference in the mean values of BP, dipping phenomenon was not significantly different in SGA
so the data for boys and girls are presented together. and AGA children (Table 3).
No difference between SGA and AGA children was
observed in terms of hypertension based on the office BP Correlations
measurements (Table 2).
A satisfactory ABPM profile was obtained in 59 (89.4%) No significant correlations were observed between the birth
of all children. In five children there were fewer than 40 weight, birth length, SDS’s and office and ABPM param-
satisfactory recordings, while in two children the recording eters in the children of the SGA and AGA groups.
Table 2 Heart rates and blood pressure of children in the SGA and AGA groups
Office BP
Systolic BP (mmHg) 102.2±11.2 103.1±9.6 0.73
SDS 0.5±0.8 0.5±0.7 0.28
Diastolic BP (mmHg) 66.4±11.8 62.8±8.3 0.17
SDS 0.7±0.6 0.5±0.7 0.24
Mean heart rates
24 h (beats/min) 89.2±12.04 90.3±12.8 0.74
Daytime (beats/min) 94.5±12.2 95.9±11.9 0.66
Nighttime (beats/min) 77.6±15.1 78.8±16.1 0.77
Systolic ABPM
24 h (mmHg) 103.2±8.7 103.5±9.3 0.89
SDS −0.2±0.7 −0.1±0.6 0.60
Daytime (mmHg) 107.6±8.8 108.5±9.6 0.70
SDS −0.5±0.8 −0.4±0.9 0.71
Nighttime (mmHg) 92.6±7.9 94.9±8.1 0.34
SDS −0.2±0.8 −0.1±0.8 0.70
Diastolic ABPM
24 h (mmHg) 62.2±6.7 62.1±5.7 0.95
SDS −0.7±0.8 −0.7±0.7 0.94
Daytime (mmHg) 64.4±7.2 65.9±5.8 0.79
SDS −0.9±0.8 −0.9±0.7 0.91
Nighttime (mmHg) 56.6±4.9 58.2±5.9 0.27
SDS −0.5±0.6 −0.6±0.7 0.58
Table 3 The frequencies of hypertension and blood pressure loads in Renal functions and biochemical evaluation
the SGA and AGA groups [n (%)]
Parameters SGA (n=35) AGA (n=24) p As shown in Table 4, serum Cr and urea concentrations
were normal in all children of both the SGA and AGA
Office BP children, and they were not different between the groups.
Systolic hypertension 3 1 0.63 According to the Schwartz formula, all children had a
Diastolic hypertension 3 0 0.26 normal GFR. The prevalence of microalbuminuria was
ABPM daytime similar in both the SGA [5.1% (2/39)] and AGA [3.7% (1/
Systolic hypertension 9 6 1.0 27)] groups (p=0.9). However, three children (2 SGA, 1
Diastolic hypertension 1 0 1.0 AGA) with normal GFR had higher microalbumin excre-
Systolic BP load 21 12 0.61 tion (30–300 mg/g Cr) and only one of the SGA children
Diastolic BP load 4 1 0.64 with microalbuminuria had systolic hypertension based on
ABPM nighttime the office BP measurements.
Systolic hypertension 1 1 1.0 The GFR was not correlated with birth weight, birth
Diastolic hypertension 1 0 1.0 weight SDS, Δ weight SDS, BMI, BMI SDS and blood
Systolic BP load 6 9 0.13 pressure parameters. Microalbuminuria, NAG and B2M
Diastolic BP load 1 2 0.56 excretion were also not correlated to birth weight, birth
ABPM 24 h weight SDS, Δ weight SDS, BMI and BMI SDS.
Systolic hypertension 5 2 0.68
Diastolic hypertension 1 0 1.0
Systolic BP load 17 9 0.43 Discussion
Diastolic BP load 3 1 0.63
Nocturnal non-dipping status Results of epidemiological studies have linked low birth
Non-dipper 8 8 0.39 weight to a raised BP in adult life, but very little data are
Systolic 7 7 0.53 available on the effect of birth weight on cardiovascular
Diastolic 6 6 0.52 dynamics and BP during childhood. Therefore, in this
prospective analysis, we have evaluated the possible
relationship between birth weight and BP parameters by
applying ABPM in 35 non-obese children born SGA and
Similarly, current height SDS, weight SDS and BMI SDS compared their data to those of 24 children born AGA. The
did not show any correlation with any of the office and results of our study do not support the existence of a
ABPM parameters in both groups. negative relationship between birth weight and BP in non-
In a linear regression analysis, office and ABPM were obese prepubertal children born SGA at term.
not associated with birth weight, birth weight SDS, Δ It has been suggested that low birth weight may have a
weight SDS and BMI SDS, all adjusted for gender. The long-term impact on the individual’s health, with an
logistic regression analysis did not reveal an independent increased risk of hypertension, cardiovascular events and
relation between office and ABPM and any parameter. altered renal function in adult life [21]. Although the
Table 4 Renal functions of the children born SGA and AGA at term at the time of the investigation
pathogenesis is still unclear, it has been proposed that fetal circadian BP regulation in SGA preterm children aged
growth retardation may be associated with impaired between 5 and 17 years. Selective increase in the nocturnal
nephronogenesis, resulting in fewer nephrons and an SBP is prominent in children with intrauterine growth
increased chance of renal disease later in life. Glomerular retardation.
hyperfiltration resulting from a reduced number of neph- It has been suggested that postnatal adaptations in
rons could lead to systemic hypertension, glomerular growth, rather than intrauterine growth restriction itself, is
sclerosis and progressive deterioration of renal function associated with an increased BP in adolescence [2, 25]. In
[22]. Nephrogenesis is a complex process that requires their longitudinal study from birth to 22 years of age, Law
many factors. Epigenetic changes lead to stable and et al. [26] showed that the lower birth weight and greater
potentially heritable changes in gene expression. The CUG rate were associated with systolic hypertension in
environmental impact on a genetic program may act on young adult life. In a large bi-racial U.S. cohort, children
the specific genetic programming of low nephron number. who crossed weight percentiles in the upward direction
This phenomenon may suggest an epigenetic effect of were found to be at an increased risk for high BP, but the
perinatal factors on the development of diseases later in life. magnitude of the effect of weight gain on BP did not
Epigenetic changes, especially methylation, have been depend on size at birth [8]. Williams et al. [7] reported that
strongly implicated in fetal renal development and diseases there was no evidence to suggest that children with a low
which appear at a later date [22]. Potential important factors birth weight who became overweight or obese had extra
influencing nephrogenesis may include activation of the high BP. In a large cohort of children aged 5–8 years,
renin–angiotensin–aldosterone system, an increase in the Bergel et al. [27] found no overall association between birth
gene expression of various tubular sodium channels, weight and BP in childhood. Nevertheless, among over-
significant reduction of enzyme 11 beta- hydroxysteroid weight children, BP was higher in those with a low birth
dehydrogenase type 2 gene and fetal glucocorticoid excess, weight than in others. Our study included only non-obese
hyperactivation of the sympathetic nervous system, inhibi- children. In our children, the lack of association between
tion of nitric oxide and insulin-like growth factor I and BP and birth weight and CUG may be due to the normal
increased serum uric acid level [23]. ranges of BMI in our children.
Many studies in adults have shown that individuals who Microalbuminuria reflects the increase in glomerular
were small at birth tend to have higher BP in later life and vascular permeability which can precede the eventual
there is an inverse relationship between size at birth and decrease in GFR [28]. NAG is located in lysosomes of
SBP later in life [24]. There is conflicting evidence on the the proximal tubular cells, and damage to these cells leads
prevalence of hypertension in children born SGA. In a to an increase in urinary NAG excretion. B2M, a low-
cohort of 891 children, there was no evidence to suggest molecular-weight protein, is freely filtered from the
that children with a low birth weight who became glomerular basement membrane and is almost completely
overweight and obese had extra high BP [7]. In a large reabsorbed from the proximal tubular epithelial cell by
bi-racial U.S. cohort, children who were SGA at term did endocytosis and catabolized by lysosomal enzymes. The
not have a greater risk of developing high BP at 7 years of level of urinary B2M increases with proximal tubular
age [8]. Rakow et al. [9] reported that BP did not differ damage and dysfunction. UB2M and UNAG excretion
between children born SGA at term and those born AGA at have been used as markers of tubulointerstitial damage and
term at a mean age of 9.8 years. Keijzer et al. [10] showed dysfunction [29]. Subtle tubular disturbances have been
that very premature birth increases SBP in young adults but reported in children and adults born SGA [30, 31]. Monge
that intrauterine growth retardation does not seem to et al. [32] observed elevated NAG excretion in children
attenuate this effect. In our study, mean BP level in children aged 4–12 years who had been born with a low birth
born SGA and AGA at term was similar. Although the weight. It has been reported that the GFR is significantly
prevalence of hypertension and elevated SBP loads were diminished and there is increased microalbuminuria in
high, there was no significant difference between SGA and young adults who were born preterm with intrauterine
AGA children. Larger SGA and AGA groups may be growth retardation [11]. Iacobelli et al. [33] suggested that
needed in future studies. In contrast, in study carried out in in premature very low birth weight infants, acute con-
Israel, 58 children aged 4–6 years with intrauterine growth ditions, such as early CUG, may affect renal outcome in an
retardation had a significantly increased BP compared with unfavorable way. Rakow et al. [9] showed that there was no
normal birth children (controls) [4]. Similarly, in a significant difference in renal function between children at
longitudinal study with children aged 5 through 21 years, 9 years of age who had been born SGA at term and those
birth weight was consistently inversely associated with SBP born AGA at term and that thee was no sign of glomerular
from childhood to young adulthood and to DBP in young and tubular damage in the SGA children. In our study, renal
adulthood [5]. Bayrakcı et al. [6] described abnormal function and urinary protein excretion were similar in the
Pediatr Nephrol (2011) 26:119–126 125
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number of children born SGA at term. However, our aim 7 years of age: results from the collaborative perinatal project.
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Acknowledgments We would like to express our gratitude to
for weight, length and head circumference at birth for given
NovoNordisk, Turkey for providing financial support for purchasing
gestational age (1977-1981). Acta Paediatr Scand 80:756–762
the kits.
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