# Cord Blood Ischemia-Modified Albumin Levels in Normal and Intrauterine Growth Restricted Pregnancies

Authors: Nicoletta Iacovidou; Despina D. Briana; Maria Boutsikou; Sophia Liosi; Stavroula Baka; Theodora Boutsikou; Demetrios Hassiakos; Ariadne Malamitsi-Puchner
Journal: Mediators of Inflammation
 (2008)

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## Abstract

Ischemia-modified albumin (IMA) is a sensitive biomarker of cardiac
ischemia. Intrauterine growth restriction (IUGR) may imply fetal hypoxia,
resulting in blood flow centralization in favour of vital organs (brain, heart,
adrenals—‘‘brain sparing effect’’). Based on the latter, we
hypothesized that cord blood IMA levels should not differ between IUGR and
appropriate-for-gestational-age (AGA) full-term pregnancies. IMA was measured
in blood samples from doubly-clamped umbilical cords of 110 AGA and 57
asymmetric IUGR pregnancies. No significant differences in IMA levels
were documented between AGA and IUGR groups. IMA levels were elevated in
cases of elective cesarean section (P = .035), and offspring of
multigravidas (P = .021). In conclusion, ‘‘brain
sparing effect’’ is possibly responsible for the lack of differences in
cord blood IMA levels at term, between IUGR and AGA groups. Furthermore, higher
oxidative stress could account for the elevated IMA levels in cases of elective
cesarean section, and offspring of multigravidas.


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## Body

## 1. Introduction

Ischemia-modified albumin (IMA) is a relatively
new biomarker in the identification of myocardial ischemia in advance or in the
absence of myocardial necrosis [1]. Since IMA can be detected before troponin
(a well-known marker of necrosis) and has a high sensitivity (82%) compared to
traditional diagnostic tools (ECG-45%, troponin-20%), it is valuable for the
diagnosis of myocardial ischemia in patients presenting with chest pain at the
emergency department [1–3]. It is well known that IMA rises within minutes from
the onset of the ischemic event and remains elevated for several hours after
cessation of ischemia [2, 3].The pathophysiological events of ischemia,
including hypoxia, acidosis, and free radical generation, result in a conformational
change of the N-terminus of albumin, leading to a reduction in its binding with
the transition metals copper, nickel, and cobalt [4, 5]. The resulting
molecule, IMA and its reduced binding of cobalt,  has been exploited to produce a
rapid automated test, the albumin cobalt binding assay [6]. Intrauterine growth
restriction (IUGR) caused by chronic malnutrition and hypoxia, (consequent to
deficient placental transport of nutrients and oxygen—asymmetrical
pattern of IUGR)—is characterized by blood flow redistribution
to vital organs (brain, myocardium, and adrenal glands), while other organs are
deprived from sufficient blood flow [7–9]. This phenomenon called “the brain
sparing effect” is usually accompanied by oligohydramnios [10, 11].Taking into account “the
brain sparing effect,” this study was based on the hypothesis that cord blood IMA
levels should not differ between IUGR and appropriate for gestational age (AGA)
full-term pregnancies. Therefore, we aimed to investigate cord blood IMA levels
in IUGR and AGA pregnancies at birth and correlate determined levels with
gestational age, gender, and mode of delivery.


## 2. Subjects and Methods

The Ethics Committee of our teaching
hospital approved the study protocol. All included mothers provided signed informed
consent before recruitment. In the time period from January 2006 to January
2007, one hundred and sixty seven parturients giving consecutively birth either
to AGA (n=110) or IUGR (n=57, birth weight below the 3rd customized centile)
full-term singleton infants were included in the study. Deliveries were
performed either vaginally or by elective caesarean section. The gestation
related optimal weight (GROW) computer-generated program [12, 13] was used to
calculate the customized centile for each pregnancy, taking into consideration
significant determinants of birth weight, such as maternal height and booking
weight, ethnic group, parity, gestational age, and gender [12].Causes of IUGR were identified in
each one of our 57 IUGR cases. Thus, 13 mothers presented with pre-eclampsia,
20 with pregnancy-induced hypertension, 3 with severe type-I diabetes mellitus,
while 21 were heavy smokers during the whole duration of pregnancy. Amniotic fluid was
diminished in all IUGR cases. For
the evaluation of the amniotic fluid, the largest fluid column on the vertical
plane was assessed and was defined as diminished, if<2 cm. Furthermore, placental
weight was reduced [14] ranging from 230 to 420 g.In
contrast, in the AGA group, mothers were healthy and were either nonsmokers or
had abstained from smoking during pregnancy. Moreover, placentas were normal in
appearance and weight.All neonates had no symptoms of
intrauterine infection or stigmata of genetic syndromes. One- and five-minute
Apgar scores were ≥8 and umbilical cord pH values were ≥7.25 in all IUGR cases
and AGA controls. The demographic data
of participating infants and mothers are shown in Table1.Table 1
Demographic data of appropriate for gestational age (AGA) and intrauterine growth
restricted (IUGR) pregnancies.
AGA Mean ± SD (Median)IUGR Mean ± SD (Median)PBirth-weight (g)3195±298.5 (3200)2595±264.5 (2630)<0.001Customized Centiles40.1±23 (35)5.7±5.2 (5)<0.001Gestational age (weeks)39.0±1.0 (39.1)38.4±1.4 (38.3)NSGender——NSMale66 (60)27 (47.4)—Female44 (40)30 (52.6)—Mode of delivery——0.022Vaginal82 (74.5)32 (56.1)—Elective Caesarean
section28 (25.5)25 (43.9)—Parity——NSFirst79 (71.8)37 (64.9)—Other31 (28.2)20 (35.1)—NS: nonsignificant.Blood was collected at birth, from
the doubly-clamped umbilical cord (UC), reflecting the fetal state.
Pyrogen-free tubes were used and samples were immediately centrifuged after
clotting. The supernatant serum was stored at−80°C until assay.IMA was measured with the albumin
cobalt binding (ACB) test (inverness medical professional diagnostics, Bedford, UK).
A cobalt solution is first added to serum, followed by addition of
dithiothreitol (DTT). DTT reacts with the cobalt to form a colour that is
measured by absorbance read spectrophotometrically. In serum of normal
patients, cobalt binds to the N-terminus of albumin, which leaves little cobalt
to react with DTT, producing a lighter colour. Conversely, in serum of ischaemic
patients, cobalt does not bind to the N-terminus of IMA, which leaves more free
cobalt to react with DTT, forming a darker colour. The ACB test is configured
to run on Roche Cobas Integra 800 instrument. The minimum detectable
concentrations, intra- and inter-assay coefficients of variation were 28 U/ml,
1.7% and 5.7%, respectively.


## 3. Statistical Analysis

Data regarding IMA were normally distributed (Kolmogorov Smirnov test). Linear
regression analysis was used to examine the effect of gender, mode of delivery,
parity, birth-weight, and gestational age on IMA levels. Student's t-test
was used to detect differences in continuous variables (IMA, birthweight,
gestational age) between IUGR and AGA groups. Mann Whitney U test was used to
detect differences in customized centiles between groups, since data regarding customized
centiles were not normally distributed. Pearson's chi square test was used to
detect differences concerning gender, mode of delivery and parity between
groups. Spearman's or Pearson's correlation coefficient were used to detect any
positive or negative correlations.P<.05 was considered statistically significant. The power calculation of the
study was 85%.


## 4. Results

Doppler studies were performed in
the IUGR group every 10–15 days, starting
from the 32nd gestational week. During each Doppler velocimetry evaluation
study, three consecutive measurements of the pulsatility index (PI) of the
studied vessel were done and the mean value was recorded. Concerning uterine
and umbilical arteries [15, 16], mean
PI values were progressively found to be in the upper physiological limits for
the corresponding gestational age in 38 cases (ranging between the 90th and the
95th percentile), while in the remaining 19 cases PI values showed increased
impedance to flow, being above the 95th percentile for gestational age.
Regarding middle cerebral arteries [17], Doppler studies showed resistance to
be in the lower physiological limits for gestational age, indicating the
initiation of blood flow redistribution process. Determined mean [95% confidence intervals (CI)]
values of cord blood IMA levels were in the AGA group 112.44 (109.95–114.92)
and in the IUGR group 115.54 (111.97–119.12). No significant differences in cord blood IMA levels were found between
IUGR cases and AGA controls. In both groups, cord blood IMA levels were
significantly elevated in cases of caesarean section (by 4.676 IU/mL on
average) compared to cases of vaginal delivery (b=4.676, CI 95%: 0.328–9.025, P=.035). Additionally, cord blood
IMA levels were significantly increased (by 5.012 IU/mL on average) in cases of
multigravidas compared to primigravidas (b=5.072, CI 95%: 0.768–9.256, P=.021). Finally, cord blood IMA levels
did not depend on gestational age or gender.


## 5. Discussion

It has been recently reported that IMA is a
highly sensitive biomarker, reflecting the myocardial ischemic condition prior
to progression to myocardial necrosis [18–20]. In this respect, IMA has been
reported to increase after percutaneous coronary interventions and in acute
coronary syndromes [1, 21]. In this setting, elevated IMA levels may result
from increased oxidative stress, caused by ischemia reperfusion injury or other
mechanisms linked to primary reduction of coronary blood flow or muscle damage
[1, 21–23].Although there is a growing body of evidence
regarding IMA in the area of monitoring acute coronary syndromes in adults
[1, 18–23], data concerning the perinatal period are sparse [24, 25]. In this
respect, higher cord blood IMA values were documented in complicated
deliveries, indicating fetal distress and/or hypoxia [24]. Furthermore,
elevated maternal serum IMA levels have been recently demonstrated in early
normal pregnancy, supporting the hypothesis that normal trophoblast development
is associated with a hypoxic intrauterine environment [25].In line with our hypothesis, the results of the
present study indicate a lack of significant differences in cord blood IMA
levels between nondistressed IUGR cases and AGA controls, suggesting no
evidence of myocardial damage in the former, possibly due to sparing of vital
organs (e.g., brain, heart) [7–9]. Similarly, previous studies of ours  reported
that circulating levels of neurotrophins, which are important for pre- and
postnatal brain development, as well as of cardiac troponin-I, which is a
highly specific indicator of myocardial damage, did not differ between asymmetric
nondistressed IUGR and AGA groups [26, 27].On the other hand, contrary to our expectations,
cord blood IMA levels were significantly elevated in cases of elective caesarean
section compared to cases of vaginal delivery. In the literature, no evidence
exists whether the fetus is subject to oxidative stress during labour [28].
Several studies have shown that umbilical arterial blood of newborns delivered
vaginally or after emergent caesarean section contains higher levels of
oxidation products than the blood of newborns delivered by elective caesarean
section [29–32]. However, other reports suggest that oxidative stress in the
fetal circulation does not depend on the mode of delivery [28]. In fact, a
recent study even found that the “reservoir” of antioxidants in the fetal red
blood cell compartment is higher in infants delivered vaginally than in those
delivered by elective caesarean section [33]. It should be noted that all neonates
included in our study were born healthy, as evaluated by Apgar scores and pH
values.Moreover, in our cohort, cord blood IMA levels
were found to depend on parity, being significantly elevated in offspring of
multigravidas. Relatively, epidemiological studies have demonstrated a
consistent relationship between the number of pregnancies and the subsequent
development of cardiovascular disease, due to an increase in oxidative damage
during late pregnancy [34, 35]. The association, found between cord blood IMA
levels at term and parity in the present study, may have important implications
in the development of atherosclerosis and long-term cardiovascular health of
women of high parity [34, 35].In conclusion, cord blood IMA levels at term do
not differ between IUGR cases and AGA controls, possibly due to the sparing of
vital organs, like the heart. Furthermore, higher oxidative stress may account
for the elevated cord blood IMA levels in cases of elective caesarean section,
as well as in the offspring of multigravidas. Oxidative stress indicated by
elevated IMA levels in women of high parity may have important implications in
their long-term cardiovascular health and warrants further investigation.



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