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Early Human Development 105 (2017) 63–67

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The potentials and limitations of neuro-biomarkers as predictors of

outcome in neonates with birth asphyxia☆
Angela Satriano b, Francesca Pluchinotta b, Francesca Gazzolo a, Laura Serpero a, Diego Gazzolo a,⁎
Dept. of Maternal, Fetal and Neonatal Medicine, “C. Arrigo” Children's Hospital Alessandria, Italy
Dept. of Cardiology and Laboratory Research, S. Donato Milanese University Hospital, Milan, Italy

a r t i c l e i n f o a b s t r a c t

Keywords: Perinatal asphyxia and its complication, hypoxic-ischemic encephalopathy, are still among the major causes of
S100B perinatal mortality and morbidity. Despite accurate standard postnatal monitoring procedures, the post-insult
Perinatal asphyxia period is crucial because at a time when radiologic pictures are still silent, brain damage may already be at a sub-
Brain damage clinical stage. Against this background, the measurement of quantitative parameters, such as constituents of ner-
Newborn vous tissue, that are able to detect subclinical lesions at a stage when routine brain monitoring procedures are still
silent, could be particularly useful.
Therefore, in the present review we report the potentials and limitations of biomarkers in predicting outcome in
neonates complicated by perinatal asphyxia.
© 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The intensity, severity and timing of asphyxia, as well as peculiar is-
chemic susceptibility and the degree of maturity of the brain, define the
About 0.1–0.4% of full-term newborns (FTN) can be affected by peri- dimension and grade of severity of the consequent damage [4]. There
natal asphyxia (PA) and its dramatic complication, hypoxic-ischemic are several circumstances in which the developing brain is especially
encephalopathy (HIE) [1]. PA-HIE accounts for 15–20% of perinatal mor- vulnerable to ischemia [5], and late preterm infants born between 34
tality and an additional 25% develop childhood disabilities. While mild and 36 weeks of gestation are known to be at highest risk of permanent
HIE is known to be at relatively low risk for motor or cognitive deficits, neurological sequelae [6]. The reason for this is that at this stage central
in severe HIE the common clinical repertoires are cerebral palsy (CP) nervous system (CNS) growth is at its peak in terms of brain weight,
and intellectual disabilities. Moreover, in moderate HIE motor deficits, volume, structure and function [6].
memory impairment and visual motor or visual perceptive dysfunction, The pathophysiological steps leading to CNS damage need to be up-
increased hyperactivity and delayed school readiness can occur [2,3]. dated: there is evidence that, in addition to the bi-phasic post-H-I insult,
HIE pathogenesis is fairly complex and still not fully understood. The the so-called third phase, which may last for weeks, months and even
developing fetal brain is highly reliant on a constant sustained blood years, has to be included [7,8]. The mechanisms of this persisting dam-
flow and, during hypoxic-ischemic insult (H-I), different intracellular age, which are still a matter of debate, involve gliosis, persistent inflam-
mechanisms are activated, which in turn lead to cell damage [4]. matory receptor activation and epigenetic changes.
The combined effects of the above pathophysiological phases act by
disrupting essential components of the cell, leading ultimately to death
Abbreviations: FTN, full-term newborns; PA, perinatal asphyxia; HIE, hypoxic-
ischemic encephalopathy; CP, cerebral palsy; H-I, hypoxic-ischemic insult; CNS, central
or apoptosis [7,8] and to a significant increase in peculiar CNS
nervous system; BM, biomarkers; GFAP, glial fibrillary acidic protein; NSE, neuron neurobiomarkers (BM) in biological fluids such as brain constituents
specific enolase; AM, adrenomedullin; FDA, food and drug administration; EMA, (activin A; glial fibrillary acidic protein, GFAP; neuron specific enolase,
european medicine agency; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; NSE; S100B) and vasoactive agents (adrenomedullin, AM).
ICH, cerebral hemorrhage; PPV, positive predictive value; NPV, negative predictive
In the present review we report the potentials and limitations of bio-
value; PLR, positive likelihood ratio; NLR, negative likelihood ratio; BBB, brain blood
barrier; HT, hypothermia. markers in predicting outcome in neonates complicated by PA.
☆ Under the Auspices of the Italian Society of Neonatology and The I.O. PhD International
Research Program
⁎ Corresponding author at: Dept. of Maternal, Fetal and Neonatal Medicine, “C. Arrigo” 2. Biomarkers: where are we?
Children's Hospital, Spalto Marengo 46, I-15100 Alessandria, Italy.
E-mail addresses: (A. Satriano), (F. Pluchinotta), In recent years there has been increased interest in the usefulness of
(F. Gazzolo), (L. Serpero), (D. Gazzolo). BMs for the early diagnosis of CNS damage, as well as for the monitoring
0378-3782/© 2016 Elsevier Ireland Ltd. All rights reserved.

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64 A. Satriano et al. / Early Human Development 105 (2017) 63–67

and evaluation of the extent of the lesion. The Food and Drug Adminis- 3.2. GFAP
tration (FDA) and the European Medicines Agency (EMA) have been
shown to support research on BMs [9,10]. The main points of interest re- A monomeric protein of the astroglial skeleton with a molecular
gard the specificity of BMs for determining the extent of CNS damage mass of 40–53 kDa located in the white and gray matter [9,10] where
and the timing of the insult. Briefly, a BM may enable clinicians to: (i) it can be released rapidly out of damaged areas and up-regulated
screen infants for brain injury with high sensitivity and specificity, (ii) through astrogliosis. Changes in blood concentrations of GFAP have
monitor the progression of disease through longitudinal monitoring, also been shown to reflect damage to the blood-brain barrier (BBB).
thanks to their short half-life, (iii) correlate the findings of BMs with
those of validated standard procedures able to diagnose brain injury 3.2.1. Potentials
and the extent of lesions, such as ultrasound and magnetic resonance GFAP has been investigated mainly in conventional biological fluids
imaging (MRI). In addition to these criteria, the new generation of (i.e. CSF, blood) of PA infants. In CSF, GFAP was assayed between 12 and
BMs in perinatal medicine have the following properties: (i) they have 48 h after birth of PA-HIE FTN. GFAP levels increased up to 5-fold in accor-
been well studied in the pediatric/neonatal population; (ii) they can dance with HIE severity [17]. Indeed, GFAP measured in the first 4 days of
be measured using kits that are commercially available worldwide, are life was significantly increased and correlated with other indicators of
simple to use and provide measurements with good reproducibility; long-term prognosis and with neurological impairment at 1 year of age,
(iii) reference ranges are available for pediatric/neonatal populations; or death before that time [17,18]. The PPV of a GFAP measurement higher
(iv) they can be assessed in different biological fluids such as urine, than the 98th percentile of normal infants was 69%, while a GFAP level
blood, cerebrospinal fluid (CSF), amniotic fluid, saliva and milk, possibly below this limit invariably predicted a good outcome [18].
reducing perinatal stress related to testing. In blood, increased GFAP levels are closely correlated with the sever-
ity of HIE. At a GFAP cut-off of 0.08 pg/mL, the PPV value was 100% and
NPV 0% for predicting infants with abnormal outcomes at 15–18 months
3. Biomarkers of age [19]. Reports also showed that GFAP at a cut-off value of
0.07 ng/mL, had a sensitivity and specificity for HIE of 77% and 78%, re-
3.1. Activin A spectively, and correlated with MRI patterns [20].

Activin A is a member of the transforming growth factor-β super- 3.2.2. Limitations

family, which in the CNS regulates neurons differentiation and prolifer- Few data are currently available regarding reference curves for GFAP
ation [10,11]. The neuroprotective action of activin A is exerted via the in different biological fluids. This is of relevance, bearing in mind that
activation of different pathways: in animal models and cell cultures GFAP is reasonably involved in CNS development and is therefore gesta-
activin A has a beneficial role in neuronal recovery, supporting the sur- tional age-dependent. Notably, data on GFAP levels in unconventional
vival of neurogenic cell lines and retinal neurons and offering protection biological fluids are still lacking, and no conclusive results have been re-
against neurotoxic damage [11]. In rats, activin A enhances neuron sur- ported regarding correlations between GFAP and cerebral ultrasound
vival, rescues against neurotoxic damage and decreases H-I injury [11]. and MRI patterns.

3.1.1. Potentials 3.3. NSE

Activin A has been measured in milk and in CSF, cord and peripheral
blood and urine of PA-HIE FTN [10]. In CSF, activin A concentrations An enzyme that catalyzes the conversion of 2-phospho-D-glycerate
were higher in PA FTN who developed severe HIE than in those who to phosphoenolpyruvate in a glycolytic pathway. It has a molecular
did not or in controls. An activin A cut-off of 1.3 pg/L as an early diagnos- weight of 78 kDa and a half-life of 24 h. In the CNS it is characterized
tic test for HIE [12] had a sensitivity and specificity of 100% with a pos- by its stable presence in mature sensory and endocrine neurons, sug-
itive predictive value (PPV) of 100% and a negative predictive value gesting that a unique system of intracellular energy metabolism may
(NPV) of 0%. Notwithstanding these promising results, the assessment be shared by neurons and paraneurons [9,10]. Immunohistochemistry
of activin A in CSF has been gradually abandoned due to the invasive shows that NSE can be traced in the cerebral circulation after experi-
sample collection procedure and stress for infants. In blood, elevated mentally induced cerebral lesions, and plasma concentrations correlat-
longitudinal activin A levels in PA-FTN correlated with impaired fetal ed with events of neuronal NSE loss in focally ischemic neurons [9,10].
circulation and hypoxia [13]. As an HIE diagnostic test an activin A NSE is also present in erythrocytes, platelets, plasmatic cells, lym-
cut-off of 0.66 ng/L achieved a sensitivity of 93.33%, a specificity of phocytes, capillary walls, and myoepithelial cells, which explains its
96.63%, with positive and negative likelihood ratios (PLR, NLR) of physiologically low concentrations in blood. NSE is secreted after cell in-
27.69 and 0.069, respectively. In both blood and CSF, activin A increased jury into the extracellular fluids, CSF and blood, where it represents an
in PA-HIE before the appearance of related clinical and laboratory signs attempt to maintain homeostasis [21].
[14]. More recently, activin A levels measured in urine were significantly
higher in PA newborns with moderate or severe HIE than in those with 3.3.1. Potentials
absent or mild HIE. An activin A cut-off N 0.08 ng/L at first void had a sen- NSE has been investigated mainly in conventional biological fluids
sitivity of 83.3% and a specificity of 100% for predicting the development (i.e. CSF, blood) of PA infants and is thought to be released into the
of moderate or severe HIE [15]. blood as a consequence of damage to BBB, or brain injury due to tissue
These observations suggest that activin A could provide additional ischemia or edema [22]. In blood, higher NSE levels were observed in
information to physicians on the occurrence of perinatal brain injuries PA-HIE FTN than in controls. At a cut-off value of N 40.0 mg/L NSE
at a stage when diagnostic procedures have a limited benefit. achieved a sensitivity and specificity as a predictor of moderate/severe
HIE of 79% and 70% respectively, and a PPV and NPV of 51% and 89%, re-
spectively. Moreover, NSE as a predictor of poor outcome at a cut-off
3.1.2. Limitations value N 45.4 mg/L had a sensitivity and specificity of 84% and 70%, and
To date, few data are available regarding the correlation of activin A a PPV and NPV of 39% and 95%, respectively [23]. Conversely, Nagdyman
levels with the extent of brain lesions, assessed using standard tech- et al. found no differences in NSE concentrations in FTN with no or mild
niques such as ultrasound and MRI, and with short-term outcomes. Ref- HIE and those with moderate or severe HIE [24]. Roka et al. [25] mea-
erence curves in the neonatal/pediatric period are requested due to the sured NSE blood concentrations in PA infants subjected to whole-body
trophic role of activin in CNS development [9–11,16]. hypothermia (HT) and found that NSE levels were highly elevated

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A. Satriano et al. / Early Human Development 105 (2017) 63–67 65

following PA, decreased during HT and were strongly correlated with well as because of the relatively low stress of the sampling procedure.
the neuro-developmental outcome at 2 years of age. S100B saliva levels increased in FT PA-HIE and correlated with the occur-
rence of abnormal MRI patterns and with adverse 1-year neurological
3.3.2. Limitations outcome. At a cut-off value N3.25 MoM, S100B achieved a sensitivity
Although NSE has been suggested as a promising biomarker in peri- and a specificity of 100% as a single marker for predicting the occurrence
natal medicine, few reports are currently available time. Among the lim- of abnormal neurological outcome [48].
itations to its use, the fact that it is unstable in all conditions in which Finally, Roka et al. measured S100B blood concentrations in PA in-
hemolysis occurs (NSE is expressed on red blood cell membranes) is fants subjected to HT. They found that S100B levels were significantly
its main weakness [9,10]. To our knowledge, investigations providing elevated following PA, decreased during HT and were closely correlated
correlations between NSE, the extent of brain lesion (MRI) and short/ with the neuro-developmental outcome at 2 years of age [25].
long-term follow-up are lacking. Furthermore, no reference curves are
yet available for the perinatal period or in different biological fluids. 3.4.2. Limitations
Of the BMs considered here, S100B is one of the most thoroughly stud-
3.4. S100B ied. Reference curves in different biological fluids (i.e. amniotic, cord and
peripheral blood, urine, saliva) have been provided [31–38]. Results show
An acidic calcium-binding protein of the EF-hand family, highly spe- that the protein is gestational age-, gender- and mode of birth delivery-
cific for CNS, where it appears to be most abundant in glial cells, dependent. However, before including S100B in daily practice there are
Schwann cells and neurons [9,10]. The protein has a half-life of 1-h some points that need further investigation. In particular: i) correlation
and is eliminated mainly by the kidneys (98%) [26]. As an extracellular with cerebral ultrasound and MRI patterns in preterm and term infants
factor, S100B engages receptors for advanced glycation end products and, ii) correlation with long term neurological outcome (≥2 years).
in a variety of cell types with different outcomes (i.e. beneficial or detri-
mental, pro-proliferative or pro-differentiative) depending on the con- 3.5. AM
centration of the protein, the cell type and the microenvironment. It
has been implicated in several cellular processes, particularly those in- It is a C-amidated peptide belonging to the calcitonin gene-related
volving calcium homeostasis and signal transduction, in which S100B peptide family, first isolated from human pheochromocytoma and in-
seems to play a dual role in the regulation of cell function, being benefi- volved in the response to hypoxia and inflammation, which are associ-
cial to cells at low doses but detrimental at high doses [27,28]. ated with neovascularization [9,10]. In the CNS, AM is expressed mainly
As a rather small protein with a molecular weight of 21 kDa in its bi- in neurons and in the endothelium, where it has been proven to have a
ologically active homodimeric form, S100B passes the BBB, and is thus role in vasodilatation, although other actions have also been reported,
detectable as a brain-derived protein in peripheral blood [29]. including neuromodulation and inhibition of apoptosis [49]. In the rat
model, AM is detectable in the hypothalamus and in the neuronal nuclei
3.4.1. Potentials of the caudate-putamen area, one of the brain areas most sensitive to
S100B has been widely studied in different biological fluids such as H\\I damage, suggesting its involvement in response to hypoxia [50–
CSF, amniotic fluid, blood, urine, saliva and milk [30–39]. More recently, 52]. The findings in animal models support the notion that AM acts as
in high-risk pregnancies the protein has been detected in fetal-maternal a neuro-protective and vascular-neuro-regenerative factor [53].
bloodstreams [40,41]. In perinatal medicine, S100B in CSF has been used
to monitor newborns affected by PA and post-cerebral hemorrhage ven- 3.5.1. Potentials
tricular dilatation (ICH) [18,19,42]. S100B correlated with the extent of AM has been shown to participate in the cascade of events promot-
brain lesions, with long-term prognosis, and with neurological impair- ing fetal/neonatal cardiovascular adaptation [9,10]. Its assessment in
ment at 1 year of age or death before that time. S100B in blood was mea- CSF and in cord and peripheral blood provides useful information in
sured hypothesizing that during active brain injury the protein may be cases complicated by PA and HIE [9,10]. Early elevated AM blood con-
released from the damaged tissue and part of it could spread into the centrations have been found to predict cases at risk for HIE and ICH
systemic circulation [43], also as a result of hemodynamic rearrange- [54]. Of note, in newborns complicated by congenital heart diseases el-
ment of the BBB. Increased S100B concentrations were detected 48– evated longitudinal AM assessment in the peri-operative period corre-
72 h before any clinical, laboratory, or ultrasound signs of cerebral hem- lated with the occurrence of adverse neurological outcome at 1-year
orrhage in FT-HIE newborns [44]. Nagdyman et al. [24] reported that follow-up [55]. AM as an early diagnostic test for adverse neurological
S100B in cord blood was already significantly higher in PA-HIE new- outcome at a cut-off of 17.4 ng/L achieved a sensitivity of 100% and a
borns. At 2-h from birth and a protein cut-off of 8.5 μg/L, the PPV of specificity of 73.0% with PLR and NLR of 3.7 and 0.0, respectively.
S100B for HIE was 71%, the NPV 90%, sensitivity was 71%, and specificity
90% [28]. S100B also correlated with abnormal cerebral hemodynamic 3.5.2. Limitations
patterns and with the extent of ICH in FT-HIE newborns [44]. Further investigation is needed to determine correlations between
In urine, longitudinal S100B measurement has also been investigated AM, the extent of a brain lesion, cerebral ultrasound and MRI patterns
in PA-HIE FTN [45–47]. An early increase in S100B levels was a predictor and short/long-term follow-up. Reference curves in neonatal/pediatric
of HIE and subsequent adverse neurological outcomes [45]. An S100B cut- patients are still lacking, although at this stage there is no evidence
off of 0.28 μg/L at first urination had a sensitivity of 100% and a specificity that AM is gestational age- and/or gender-dependent.
of 87.3% for predicting adverse 1-year neurological follow-up. The sensi-
tivity and specificity of measurements obtained from 12 to 72 h after 4. Conclusions
birth were up to 100% and 98.2%, respectively. PPV and NPV were 46.2
and 100%, respectively. Moreover, elevated S100B levels have been According to FDA and EMA requirements further progress is needed
shown to represent a marker of brain damage and HIE. An S100B cut-off before BMs or combinations of BMs can become daily practice in NICUs.
of 0.41 μg/L at first urination had a sensitivity of 91.3% and a specificity However, as for adult and pediatric diseases we are not so far [56–58].
of 94.6% for predicting the development of HIE. The sensitivity and spec- There are still a few issues that need to be addressed: the most regard
ificity of measurements obtained from 4 to 72 h after birth were up to the different techniques for assessing BMs (i.e. ELISA, LIASION, HPLC)
100% and 98.8%, respectively. PPV and NPV were 80.8 and 97.8 respective- in terms of reproducibility, sensitivity, specificity and optimal timing
ly [46]. More recently, S100B has also been detected in saliva which is the for obtaining results. This latter issue is crucial for the selection of pa-
preferred fluid option in terms of timing and longitudinal collection, as tients suitable for treatment and to employ neuro-protective strategies

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66 A. Satriano et al. / Early Human Development 105 (2017) 63–67

Table 1
Optimality items for a biomarker (BM) according to the following international criteria: marker of brain damage and of degree and extension of the lesion; possibility of longitudinal mon-
itoring; studied in pediatric/neonatal populations and provided of reference curves; measurable by commercial kits; measurable in different biological fluids.

BM Brain Damage Degree of injury Lesion Extension Longitudinal Monitoring Pediatric Population Available kit Reference curve Biological fluid

Activin A Y Y Y Y N Y N CS, A, C, P, U
S100B Y Y Y Y Y Y Y CS, A, C, P, U, S
AM Y Y Y Y N Y N CS, A, C, P

Abbreviations: GFAP, glial fibrillary acid protein; NSE, neuron specific enolase; AM, Adrenomedullin; Y, yes; N, no; CS, cerebrospinal; A, amniotic; C, cord blood; P, peripheral blood; U,
urine; S, saliva.

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