PEDIATRICS Vol. 118 No. 3 September 2006, pp. e747-e754 (doi:10.1542/10.1542/peds.2005-2875)
ARTICLE |
Urinary S100B Protein Concentrations Are Increased in Intrauterine Growth-Retarded Newborns
a Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Siena, Italy
b Laboratory of Perinatal Medicine and Molecular Biology, Department of Obstetrics and Neonatal Health, "La Sapienza" University, Rome, Italy
c Department of Neonatology, University Hospital, Cairo, Egypt
d Department of Pediatrics, Obstetrics and Gynecology, and Neuroscience, Giannina Gaslini Children's University Hospital, Genoa, Italy
e Institute of Anatomy and Cell Biology, Catholic University, Rome, Italy
f Department of Fetal and Neonatal Medicine, G. Garibuldi Hospital, Catania, Italy
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND. Intrauterine growth retardation is one of the major causes of perinatal mortality and morbidity. To date, there are no reliable methods to detect brain damage in these patients.
METHODS. We conducted a case-control study in tertiary NICUs from December 2001 to December 2003 with 42 intrauterine growth retardation infants and 84 controls. Routine laboratory variables, neurologic outcome at 7-day follow-up, ultrasound imaging, and urine concentrations of S100B protein were determined at 5 time points. Urine S100B levels were measured by an immunoluminometric assay at first urination, 24, 48, and 72 hours, and 7 days after birth. Routine laboratory parameters and neurologic patterns were assessed at the same time as urine sampling.
RESULTS. S100B protein was significantly higher at all of the monitoring time points in urine taken from intrauterine growth retardation newborns than in control infants. When intrauterine growth retardation infants were corrected for the presence of abnormal (group A) or normal (group B) neurologic examination 7 days after birth, S100B was significantly higher at all of the predetermined monitoring time points in group A infants than in group B or controls. At a cutoff of 7.37 multiples of median at first urination, S100B achieved a sensitivity of 95% and a specificity of 99.1% as a single marker for predicting an adverse neurologic outcome. Twenty of 126 patients had neurologic abnormalities, making an overall prevalence of the disease in our population of 15.9% (pretest probability). With respect to the performance of S100B in predicting brain damage, its positive and negative predictive values were 91.0% and 99.0%, respectively.
CONCLUSIONS. Increased urine S100B protein levels in intrauterine growth retardation newborns in the first week after birth suggest the presence of brain damage reasonably because of intrauterine hypoxia. Longitudinal S100B protein measurements soon after birth are a useful tool to identify which intrauterine growth retardation infants are at risk of possible neurologic sequelae.
Key Words: brain damage • brain protein • S100B protein • newborn • IUGR
Abbreviations: IUGR—intrauterine growth retardation • CNS—central nervous system • SNAP-PE—Score for Neonatal Acute Physiology-Perinatal Extension • MoM—multiples of median • ROC—receiver operating curve • CI—confidence interval
Intrauterine growth retardation (IUGR) is a multicause condition that does not allow the fetus to reach his potential of growth. IUGR may be considered the consequence of a disease process within 
1 of the 3 compartments that sustain and regulate fetal growth: the maternal compartment and the placenta. IUGR is in most cases secondary to uteroplacental insufficiency (
50%) because of impaired trophoblast invasion of spiral arteries, which are not transformed to low-resistance vessels.1,2 IUGR can complicate 
10% to 15% of physiologic pregnancies, and it is associated with perinatal mortality and with 40% of neurologically handicapped children.3 Indeed, fetoplacental insufficiency and subsequent fetal hypoxia activate a cascade of pathophysiological events leading to brain damage.4–6 On this regard, several clinical evidences have suggested that fetal preexposure to adverse intrauterine conditions, such as decreased oxygen and substrate supply that occurs in IUGR, plays a causal role in perinatal mortality and central nervous system (CNS) injury.3 Therefore, the possibility to monitor infants with IUGR in the early postnatal period, using brain constituents, could, therefore, be useful in detecting case subjects at risk of adverse neurologic outcome.
S100B is an acidic calcium-binding protein with a molecular weight of 21 kd, mainly concentrated in the central nervous system, in the glial cells, and in restricted neuron subpopulations. Although its biological role has not been completely clarified, it has been reported to regulate several cellular functions (cell-cell communication, cell growth, cell structure, energy metabolism, contraction, and intracellular signal transduction) at physiologic concentrations, whereas it has been shown to be neurotoxic at high concentrations.7
Elevated S100B concentrations in biological fluids, such as cerebrospinal fluid, cord blood, peripheral blood, and urine have also been shown to represent a marker of brain damage.8–14 In this respect, because S100B is mainly eliminated by the kidneys,15 data relating to the urine of newborns developing intraventricular hemorrhage and adverse neurologic outcome support the expedience of the clinical use of repeated S100B measurements in these patients.11–14
Therefore, in this study, we investigated the usefulness of longitudinal S100B assessments in urine as a tool for the early detection of brain damage in IUGR newborns, because among biological fluids, urine seems to be the most suitable, it can be collected easily, and sampling can be repeated without risk for the newborn.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Informed consent was obtained from all parents of the patients before inclusion in the study, and the approval was obtained from the human investigations committees of the participating institutions. We performed a case-control study in 4 tertiary NICUs from December 2001 to December 2003 of 42 infants with IUGR born between 30 and 39 weeks' gestation. This decision was based on the number of deliveries at our centers (
13000 per year) and epidemiologic studies relating to the incidence of IUGR in our countries. IUGR was defined by the presence of ultrasonographic signs (biparietal diameter below the 10th centile and abdominal circumference below the 5th percentile) according to the normograms of Campbell and Thoms16 and a fall in the centile of fetal size recorded between the first scan after referral and the final scan before delivery. Fetal growth restriction was confirmed by a birth weight below the 10th percentile in all of the fetuses. The control group consisted of 84 normal newborns matched for gestational age (range: 30–40 weeks' gestation; n = 24 from 30–32 weeks; n = 20 from 33–35 weeks; n = 24 from 36–38 weeks; n = 16 from 39–40 weeks), with birth-weights between the 10th and 90th percentiles (2 controls for each IUGR newborn). Infants admitted to the study fulfilled all of the following criteria: no maternal illness, no signs of fetal distress, pH >7.2 in cord blood or venous blood, and Apgar scores at 1 and 5 minutes >7. In all of the cases, the gestational age was determined by clinical data and by a first-trimester ultrasound scan. Exclusion criteria were multiple pregnancies and maternal alcohol or cocaine addiction, infants with any malformation, and cardiac or hemolytic disease. In IUGR and control infants, clinical and laboratory parameters were recorded at admission to NICUs and at 24 and 72 hours from birth for the standard assessment (ie, red blood cell count, glycemia, urea, creatinine, and ion concentration).
S100B protein levels in urine were measured at first urination (time 0), 24 hours (time 1), 48 hours (time 2), 72 hours (time 3), and 7 days after birth (time 4). The first urination occurred within the first 6 hours after birth (mean 3 hours). The control group included only infants in whom spontaneous urination occurred 4 times during the collection time: time 0 (n = 77), time 1 (n = 76), time 2 (n = 79), time 3 (n = 73), and time 4 (n = 75). In our departments, healthy infants are discharged from the hospitals after 72 hours from birth. Furthermore, because this was a case-control study, we asked and obtained consent to clinically check healthy patients also at seventh day.
The results were correlated with the presence or absence of adverse neurologic follow-up at day 7 after birth. Cerebral ultrasound and neurologic patterns were assessed at the same time as urine sampling by a single examiner in each center who did not know the results of the urine test. Finally, the severity of illness in the first 24 hours after birth was measured using the Score for Neonatal Acute Physiology-Perinatal Extension (SNAP-PE).17
Cranial Assessment
Standard cerebral ultrasonography was performed using a real-time ultrasound machine (Acuson 128SP5, Acuson, Mountain View, CA) with a transducer frequency emission of 3.5 MHz. The occurrence of cerebral hemorrhage was classified according to Papile et al.18 In controls, cerebral ultrasound patterns were recorded before discharge from the hospital.
Neurodevelopmental Outcome
Neurologic examination was performed at the same time points as urine sampling and at day 7 follow-up. Neonatal neurologic conditions were classified using a qualitative approach as described by Prechtl,19 assigning each infant to 1 of 3 diagnostic groups: normal, suspect, or abnormal. An infant was considered to be abnormal when 1 of the following neurologic syndromes were present: hyperkinesia or hypokinesia, hypertonia or hypotonia, hemisyndrome, apathy syndrome, or hyperexcitability syndrome. An infant was classified as suspect if only isolated symptoms were present but no syndrome was defined.
S100B Measurement
Urine samples were collected at each time point, immediately centrifuged at 900g for 10 minutes, and the supernatants stored at –70°C. S100B concentrations were measured in all of the samples by immunoluminometric assay (Lia-mat Sangtec 100, AB Sangtec Medical, Bromma, Sweden). According to the manufacturer's instructions, this assay is specific for the ß-subunit of the S100 protein and measures the ß-subunit as defined by the 3 monoclonal antibodies SMST 12, SMSK 25, and SMSK 28. The ß-subunit of the S100 protein is known to be predominant (80%–96%) in the human brain.20,21 Each measurement was performed in duplicate according to the manufacturer's recommendations, and the averages were reported. According to the manufacturer's instructions, the sensitivity of the assay (B0 ± 3 SD) was 0.02 µg/L, and the coefficient of variability was 5.5% within assay and 10.1% interassay for concentrations ranging between 0.28 and 4.17 µg/L.
Statistical Analysis
S100B urine concentrations were corrected for gestational age by conversion to multiples of median (MoM) of the healthy controls of the same gestational age. The control group (healthy infants) was stratified by gestational age, and the medians of each stratum were used to convert all of the values to MoM. Patients were matched with control medians according to gestation length at the time of urine sampling. S100B (micrograms per liter) concentrations were divided by the median values of control groups belonging to the same gestation period. This method improves statistical power and permits external validation of results from different populations, besides allowing regression analysis of the data to reach a day-by-day estimate of expected normal protein concentrations. The results in urine fluid were expressed as medians and ranges (lower and upper 95% confidence intervals), and differences between groups were assessed by Mann-Whitney U test.
Data on neonatal outcomes and laboratory parameters were analyzed by Turkey 1-way analysis of variance and Mann-Whitney U test when not normally distributed. Comparison between proportions was performed using Fisher's exact test. Multiple forward stepwise regression analysis was performed with S100B as the dependent variable to analyze the influence of various clinical parameters (renal function, gender, gestational age, maternal antenatal steroid treatment, presence or absence of antenatal infection, normal or abnormal neurologic follow-up at 1 week of age, presence or absence of IUGR, delivery mode, Apgar scores at 1 and 5 minutes, birth weight, and incidence of respiratory distress syndrome) on S100B.
The sensitivity, specificity, predictive value, and likelihood ratios of S100B as a diagnostic test for the detection of brain damage in IUGR newborns were assessed by using the receiver operating curve (ROC) test.22 Therefore, the probability of developing a poor neurologic outcome after having none, one, or both tests positive (higher than the cutoff point) was, thus, estimated and compared with the pretest probability, defined as the prevalence of brain damage in the whole group of newborns.23
Statistical analysis was performed by using the GraphPad Prism 3.00 for Windows (GraphPad Software, Inc, San Diego, CA), and statistical significance was set at P < .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The characteristics of the groups examined are shown in Table 1. As expected, birth weight was lower in the IUGR group than in controls. The incidences of cesarean section, respiratory distress syndrome, patent ductus arteriosus, maternal antenatal glucocorticoid treatment, and the need for mechanical ventilation support did not differ between the IUGR group and controls (P > .05 for all). At admission to NICUs, no significant differences in laboratory parameters were found between IUGR and controls (Table 2), as well as at 24 and 72 hours after birth (P > .05 for all; data not shown). SNAP-PE scores measured in the first 24 hours after birth showed significantly (P < .0001) higher values in IUGR than in healthy newborns (Table 1).
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Neurodevelopmental Outcome and Cerebral Ultrasound Findings
At birth, Prechtl's19 neurologic score was negative for overt neurologic syndromes, and 5 of 42 infants with IUGR were classified as suspect (hypertonia-hypotonia: n = 3; hyper-excitability: n = 2). The same neurologic patterns were observed at 24 and 48 hours from birth. At 7 days from birth, 11 of 42 infants with IUGR showed neurologic abnormalities, including hypertonia-hypotonia (n = 5), dystonia (n = 3), and hyperexcitability (n = 3). Isolated symptoms were also present in 9 infants with IUGR, including hypertonia-hypotonia (n = 3), dystonia (n = 3), and hyperexcitability (n = 3).
Cerebral ultrasound patterns in infants with IUGR were negative at birth and at 24 and 48 hours from birth. Seven of 42 infants with IUGR developed intraventricular hemorrhage between 48 and 72 hours from birth of grade I (n = 3), grade II (n = 3), and grade III (n = 1). No other ultrasound patterns suggestive of cerebral bleeding or cerebral diseases were found in IUGR newborns between 72 hours and 1 week from birth. Therefore, according to Prechtl's19 neurologic examination and cerebral ultrasound findings at 7 days from birth, IUGR newborns were subgrouped as suspected or pathologic (group A: n = 20) and normal IUGR (group B: n = 22).
Urine S100B Levels and the Prediction of Brain Damage
At all of the monitoring time points, S100B levels were significantly (P < .05) higher in IUGR newborns than in controls (P < .001 for all; Tables 3 and 4) and significantly higher in IUGR group A than in IUGR group B or controls (P < .001 for all) and in IUGR group B than in controls (P < .001; Table 3). Multiple forward stepwise regression analysis with S100B as a dependent variable showed a positive correlation with the occurrence of IUGR and abnormal neurologic follow-up at 1 week of age (P < .001 for both), whereas no significant correlations were found with renal function (P = .911), the presence or absence of antenatal infection (P = .680), gender (P = .884), maternal antenatal steroid treatment (P = .987), and SNAP-PE score (P = .719).
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Table 5 shows the predictive values of S100B protein levels at different monitoring time points for the occurrence of neurologic abnormalities in infants with IUGR. As can be seen, the higher S100B values as a diagnostic test were observed at first urination at the cutoff 7.37 MoM, because at this value S100B achieved a sensitivity of 95% (95% confidence interval [CI]: 75.1%–99.2%) and a specificity of 99.1% (95% CI: 94.8%–99.8%) as single marker for the prediction of occurrence of brain damage (area under the ROC curve: 0.996; Fig 1), with a positive and negative likelihood ratio of 100.7 and 0.05, respectively. Predictive values of S100B levels at fixed cutoffs of 5, 6, and 7 MoM were also calculated (Table 5). In contrast, SNAP-PE scores at the cutoff of 56 combined a sensitivity of 65% (95% CI: 40.8%–84.5%) with a specificity of 84.9% (95% CI: 76.6%–91.1%) for prediction of brain damage (area under the ROC curve: 0.822; Fig 1) and a positive and negative likelihood ratio of 4.31 and 0.41, respectively (data not shown).
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Twenty of 126 patients had neurologic abnormalities, making an overall prevalence of the disease in our population of 15.9% (95% CI: 0%–22%). This was the predicted probability of developing brain damage before S100B measurement was performed (pretest probability). With respect to predicting brain damage, if only S100B was available, the positive predictive value was 91.0% (95% CI: 78.2%–100%) and the negative predictive value 99.0% (95% CI: 97%–100%), respectively. If only SNAP-PE computation was available, its positive and negative predictive values were 44.8% (95% CI: 18%–72%) and 92.8% (95% CI: 87.5–95.5%), respectively.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The present study shows that S100B levels in urine are increased in infants with IUGR at birth and that IUGR newborns with abnormal neurologic outcome have highest urine S100B levels, higher than controls or infants with IUGR with uneventful neurologic follow-up. The relevance of such an increase in urine of IUGR newborns with or without abnormal neurologic outcome warrants considerations. Indeed, S100B is a protein mainly concentrated in the CNS7 and mainly eliminated by the kidney15; therefore, the findings of increased S100B levels into urine lead us to support the idea that they derive from the systemic circulation. S100B is a marker of brain damage in adults and in the perinatal period8–14,24–26: the continuous release of the protein from the damaged nervous tissue is the main cause of the high levels of S100B in blood and urine collected from preterm and term infants developing hypoxic ischemic encephalopathy12–14 and in the blood of IUGR fetuses with chronic hypoxia.6 Furthermore, animal data have shown that fetal hypoxemia is associated with persistent elevations in plasma S100B concentrations and, therefore, suggested S100B as a possible early marker of fetal hypoxia.27
These findings and the evidence that urine levels of S100B at the first urination and during the first 7 days of life were particularly high in IUGR newborns with abnormal short-term neurologic outcome together suggest that levels of S100B may reflect the extent of brain damage after perinatal asphyxia insult. The lack of difference in renal function parameters between IUGR newborns and controls supports the concept that S100B levels in the urine are affected by its concentration in the urine and not by a putative renal dysfunction. Another source of this protein in newborns is the placenta28; however, because the half-life of this protein is 1 hour,7 placental production might affect the first urination but is certainly not responsible for the levels found at later time points.
The elevated S100B concentrations in the urine of IUGR newborns without clinical brain damage would also support the idea that the persistently high levels of S100B could be related to brain damage, albeit at a subclinical stage. Indeed, the majority of long-term neurologic disabilities in IUGR patients cannot be detected within the first years of age by standard monitoring procedures but are diagnosed later, between the first year of admission to primary school and beyond.29 In this regard, studies of neurobehavioral and cognitive outcomes in 20-year-old boys who were IUGR newborns showed poorer school performance at 12 and 18 years.30 Therefore, the finding of increased urine levels of S100B in infants with IUGR is of relevance, because it may offer additional support in the debate about the early detection of cases at risk of altered cognitive and long-term neurodevelopmental outcome.29
With respect to short-term neurologic follow-up, we have found highest urine S100B levels in IUGR newborns with abnormal neurologic outcome 7 days after birth. It is well known that at nanomolar concentrations S100B stimulates neurite outgrowth and enhances survival of neurons during development,31 whereas micromolar levels of extracellular S100B in vitro stimulate the expression of proinflammatory cytokines and induce apoptosis.32,33 On the other hand, cell-based and clinical studies have implicated S100B in the initiation and maintenance of a pathologic, glial-mediated proinflammatory state in the CNS.34 Overexpression of S100B increases vulnerability to cerebral hypoxic-ischemic injury, because S100B transgenic mice subjected to hypoxia-ischemia showed a significant increase in mortality, more extensive cerebral injury, and neuroinflammation in response to injury.34 Therefore, the possibility that some of the S100B derives from this process and participates in the pathologic cascade of events responsible for brain damage should also be taken into account. In any case, measuring S100B in urine of newborns at a stage when standard diagnostic procedures are still silent or of no avail yields positive and negative predictive values with respect to the possibility to early detect which infants with IUGR are at risk of neurologic sequelae. Indeed, we found that newborns with urine S100B levels above the thresholds defined by the ROC curve analysis (7.37 MoM) had a probability (positive predictive value) to have neurologic sequelae as high as 91%, and 1% if they were unaltered, sharing a positive and negative predictive value that differs from the overall prevalence of the disease (15.9%) in the study population. This finding seems to be relevant, because neurologic examination and other standard monitoring procedures at this stage were unable to detect which infants with IUGR would develop an adverse neurologic outcome and which would not. In this setting, useful information might be offered by cerebral MRI, especially for detecting small brain injuries (ie, slight bleeding).35 Unfortunately, because of infrastructure limitations, we were not able to perform MRI at this early stage; however, factors such as stress because of transport from NICUs to the magnetic resonance area would have to be taken into account, especially in high-risk newborns who are intubated and supported by mechanical ventilation. Additional significant factors are the high cost of performing MRI and the technical and ethical implications of repeated assessments. However, future studies to investigate correlations between cerebral MRI patterns and the evaluation of brain constituents in different biological fluids will constitute a useful tool in early brain damage detection.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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S100B levels are highest in urine samples collected from newborns with a poor short-term neurologic outcome, and their measurement in urine, which is much more easily collectable than blood or CSF, may be of clinical help in early select fetuses at higher risk of postnatal neurologic sequelae, at a time when standard clinical and laboratory parameters are of no avail.
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ACKNOWLEDGMENTS |
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This work was partially supported by grants to Dr Michetti from Ministero dell'Università e Ricerca Scientifica e Tecnologica (MURST), Ministero della Salute, and Università Cattolica del Sacro Cuore-Roma; to Dr Gazzolo from Consiglio Nazionale delle Ricerche, MURST, and the "Let's Improve Prenatal Life" Foundation; and to Dr Petraglia from MURST and the University of Siena.
We thank Sangtec Medical, Bromma, Sweden, and Byk Gulden Italia for supplying analysis kits.
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FOOTNOTES |
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Accepted Mar 22, 2006.
Address correspondence to Diego Gazzolo, MD, PhD, Department of Pediatrics, Giannina Gaslini Children's University Hospital, Via Guglielmo Oberdan 80/1, 16167 Genoa, Italy. E-mail: dgazzolo{at}hotmail.com
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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