Indian J Pediatr
DOI 10.1007/s12098-013-1328-9
EDITORIAL COMMENTARY
Systemic Effects of Perinatal Asphyxia
Anuj Bhatti & Praveen Kumar
Received: 17 December 2013 / Accepted: 26 December 2013
# Dr. K C Chaudhuri Foundation 2014
Perinatal asphyxia is one of the three most important causes of
neonatal mortality and morbidity [1]. It is a major contributor
to long term neurodevelopmental sequele in the developing
world. During fetal hypoxia-ischemia, ‘diving reflex’ shunts
blood from ‘non-vital areas’ such as skin and splanchnic
circulation to the ‘vital organs’ like heart, adrenals, and brain
to protect them from injury. Thus theoretically, any newborn
with neurological injury due to asphyxia should also have
derangements of the ‘non-vital organs’ like kidney and gut.
However, even in cases of severe intrapartum asphyxia, the
involvement of various organs is not consistent and ranges
from 70 to 100 % [2, 3]. There could be multiple reasons
behind this variation: (a) all organs may not be equally in-
volved due to variable activation of ‘diving reflex’ [4], (b) use
of different criteria to define multi-organ dysfunction (MOD)
and asphyxia, and (c) variable timing of clinical and labora-
tory evaluation. The American Congress of Obstetricians and
Gynecologists (ACOG) uses MOD as one of the contributory
rather than essential criteria to determine the intrapartum
timing of insult [5].
Although renal, cardiac, pulmonary, hepatic and gastroin-
testinal systems could all be affected by perinatal asphyxia,
heart and kidneys are the two most important extra-cerebral
organs involved. The incidence of renal injury is 50–72 %
while cardiac injury has been seen in 29–78 % in various
studies. Damage to these organs can be persistent and may
predict outcomes [6]. Renal injury in neonatal encephalopathy
is associated with more severe brain injury and adverse long-
A. Bhatti
Department of Pediatrics, Government Medical College, Jammu,
India
P. Kumar (*)
Department of Pediatrics, Post Graduate Institute of Medical
Education and Research, Chandigarh 160012, India
e-mail: drpkumarpgi@gmail.com
term neurodevelopmental outcome [7]. Hence, it is important
to be able to make an early and reliable diagnosis of hypoxic-
ischemic injury to these organs.
Cardiac injury has been diagnosed on the basis of clinical
grounds, echocardiography, electrocardiography (ECG) and
elevation of cardiac enzymes. Echocardiography is most com-
monly used to assess myocardial dysfunction though C-
troponin-T has emerged as a marker having good correlation
with severity and outcome. ECG criteria for cardiac injury in
perinatal asphyxia have been described but are cumbersome to
apply [8]. Moreover, there are technical difficulties in record-
ing and interpreting ECGs in sick newborns. Traditionally,
ECG criteria have used T/QRS ratio and changes in ST
segment to evaluate myocardial ischemia in asphyxiated new-
borns. P-wave dispersion has been used to evaluate the dis-
continuous propagation of sinus impulse and predict atrial
fibrillation in adult patients with anterior wall myocardial
infarction [9]. The incidence of atrial fibrillation secondary
to intrapartum asphyxia in the newborn is, however, not
known. In this issue of the journal, Amoozgar et al. have
attempted to understand the changes in P-wave dispersion in
asphyxiated neonates [10]. They have also attempted to relate
P-wave dispersion with severity of asphyxia, arrhythmias,
Apgar scores and C-Troponin I. The research idea is novel
as the effects of perinatal asphyxia on cardiac conduction
system are not well described. Unfortunately, because of
several flaws in design, methodology and analysis, reliable
conclusions cannot be drawn from this study. It is not clear if
all 4 of the listed criteria had to be met or any one was good
enough for a diagnosis of asphyxia. The inclusion criteria for
controls mention the requirement of a normal neurological
examination at birth and first week. The ECGs were however
recorded on day 3. It is not clear if and how many of the
‘enrolled’ infants were subsequently excluded. The authors
chose a snapshot window on day 3 of life to look at the ECGs.
However, the changes in the ECG are dynamic and may be

transient. The understanding of the clinical significance of
these ECG changes requires a continuous Holter monitoring
to look for arrhythmias. A cohort study design with
continuous ECG recording right from birth would have
been more sensitive and objective. The representation of
data and analysis leaves much to be desired. In Table 1,
grade of asphyxia, which is an ordinal variable, has
been dealt with as a continuous variable. Many of the
variables with skewed distribution have been tackled as
if they were normally distributed. Figure 2 is mislabeled
as ROC curve, actually it is same as Fig. 1 and basi-
cally both show the distribution. These figures tell us
that there is a wide overlap between the distribution of
P wave dispersion values in the two groups and it has
poor specificity.
Similar to cardiac injury, acute kidney injury (AKI) has no
well defined definition in neonates. Adaptations from adult
AKI criteria (e.g., RIFLE and AKIN) have been tried in
neonates. The parameters used in these AKI criteria are urine
output and serum creatinine, which are unreliable in
first 48 h of life. The study by Karlo et al. in this issue
of the journal which has combined clinical, blood and
urine parameters to evaluate renal functions in neonates
with birth asphyxia, also used the same AKI criteria and
hence is unable to predict renal injury in the first 48 h
of life [11]. Use of oliguria and serum urea and creat-
inine as markers of renal injury is hampered by the fact
that there is a ‘lag’ period between the onset of injury
and abnormalities in serum creatinine and urine output.
So, in order to bridge that gap, the researchers have
tried to find a urine or serum biomarker. Use of urine
β2 microglobulin as marker of tubular dysfunction in
birth asphyxia is well described in literature. In fact, the
attempt of combining these parameters by the authors is
not novel. Aggarwal et al. have used renal function
tests, calculated renal indices using timed urine collec-
tions and excretion of β2 microglobulin and N-acetyl-b-
D-glucosaminidase (NAG) in first 4 d of life to assess
renal functions in asphyxiated neonates [12]. Karlo
et al. do not clearly mention if the urine samples were
timed collections or spot samples. Because of the tech-
nical difficulties, shorter duration collections have been
suggested and used in newborns, especially to calculate
the various renal indices. One would have liked to see a
table of comparison of baseline variables between the
cases and controls. It is apparent from the tables that
many of the variables esp. urinary β2 microglobulin, creati-
nine, sodium and renal indices had skewed distributions. Their
distribution would have been better represented by median
and interquartile ranges. Other potential new biomarkers
which have been recently tested in neonatal AKI are neutro-
phil gelatinase—associated lipocalin (NGAL), osteopontin,
cystatin C, epithelial growth factor, uromodulin (UMOD),
Indian J Pediatr
interleukin—18, liver type fatty acid-binding protein, and
kidney injury molecule 1. Among them, urinary cystatin C
and serum and urinary N-GAL have shown promise [13].
These biomarkers need evaluation in asphyxiated neonates.
In summary, both the papers [10, 11] are replete with
incorrect and loose usage of many statistical terms and
figures. Many of the statistical tests of significance have
been used inappropriately without taking the type of
data and its distribution into consideration. As a result,
substantial interpretations cannot be made. They howev-
er, do remind us that we still do not have reliable early
diagnostic markers for organ injury following hypoxia-
ischemia. We need large prospective multi-site cohort
studies with uniform definitions and serial evaluations
and follow-up to test the new biomarkers in asphyxiated
neonates.
Contributions AB: Did the literature search and formulated the draft;
PK: Conceptualized the draft, critically evaluated, revised and finalized
the manuscript. He will act as guarantor for this paper.
Conflict of Interest None.
Role of Funding Source None.
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