the association between prenatal doppler ultrasound...
TRANSCRIPT
The association between prenatal Doppler
ultrasound measurements and postnatal tissue
oxygenation in intrauterine growth restricted
(IUGR) infants.
M.R. Boelen
1826077
Beatrix Children’s Hospital - Division of Neonatology
(Department of Obstetrics and Gynaecology)
University Medical Center Groningen, Groningen
Supervisor: Prof. Dr. A.F. Bos ([email protected])
Faculty Supervisor: Prof. Dr. A.F. Bos ([email protected])
February 18th
2013 – July 8th
2013
2
Dankwoord
Allereerst wil ik Prof. Dr. A.F. Bos bedanken voor de bijzondere mogelijkheid mijn
onderzoek te mogen doen binnen de afdeling Neonatologie. Ook wil ik hem bedanken
voor zijn vele positieve aanmoedigingen, zijn hulp en zijn vele complimenten aan mij
gedurende het onderzoek.
Daarnaast wil ik MDPhD-studente J.C. Tanis bedanken voor de geweldige uitleg en
uitgebreide inwerkperiode met betrekking op het onderzoek. Ook tijdens het onderzoek
kon ik voor vragen goed bij haar terecht.
Vervolgens wil ik Drs. L. Casarella bedanken voor haar enorme inzet en prettige
aanwezigheid tijdens de echo Doppler metingen.
Afsluitend zou ik uiteraard alle moeders (en vaders) willen bedanken die bereid waren
mee te doen in dit onderzoek en mij zo de kans gaven het onderzoek voort te mogen
zetten.
3
Abstract
Background: Intrauterine growth restricted (IUGR) fetuses are at risk of mortality and
neonatal morbidity. IUGR often leads to a redistribution of the fetal circulation. Blood
flow to the brain is relatively spared, whereas that to the abdominal organs is reduced. It
is unknown how the distribution of the circulation changes after birth in IUGR infants.
Aim: To determine the relation between the Doppler ultrasound measurements in IUGR
fetuses and the distribution of the circulation in IUGR infants up to three days after birth.
Methods: Prospectively we included IUGR infants immediately after birth, of whom the
mothers were monitored because of suspected IUGR at the Department of Obstetrics and
Gynaecology in the UMCG between May 2012 and July 2013. Inclusion criteria were all
gestational ages up to of 42 weeks, and the fetuses having an abdominal circumference
below the 10th
percentile. We excluded fetuses and children with chromosomal
abnormalities, syndromes and congenital infections. From the moment IUGR was
diagnosed we performed Doppler ultrasound measurements weekly, and calculated the PI
of the fetal umbilical artery, middle cerebral artery and ductus venosus. After birth we
performed NIRS measurements during the first 3 days, for two hours continuously on
each day. As outcome measures we used multisite NIRS values, i.e. rSO2, transcutaneous
SO2 (SpO2), and calculated the fractional tissue oxygen extraction (FTOE) in cerebral,
renal and abdominal (splanchnic) tissue. Additonally we calculated the rSO2- and FTOE-
ratios between several organs. Then, we calculated correlation coefficients between the
PI values of the last fetal measurement before birth and the NIRS values including the
ratios after birth, using Spearman’s rank order correlation test.
Results: We included 21 infants with a median gestational age of 38 weeks (interquartile
range IQR 37-39), a median birth weight of 2195 grams (1925-2535) and a median
cerebral circumference of 31 cm (30-32). All infants had a birth weight <P10. Before
birth, the median z-score of the PI umbilical artery was 1.67 (IQR: 1.30-2.66), the median
z-score of the PI middle cerebral artery was -0.48 (-1.51-0.66) and the median z-score of
the PI ductus venosus was 2.26 (0.81-5.91) On day 1, 21 infants were measured by
multisite NIRS, these were 19 infants on day 2 and 16 infants on day 3. We found several
significant correlations between the Doppler ultrasound measurements before birth and
the NIRS measurements after birth, the strongest of them on day 1 and 2. The PI-ductus
venosus correlated strongly with SpO2 on day 1 (Spearman’s ρ: 0.635). The PI-ductus
venosus correlated postively and moderately strong with renal NIRS measurements on
day 3 (ρ: 0.657) The PI-middle cerebral artery correlated negatively with the cerebral
NIRS on day 3. Regarding the NIRS ratios, we only found a strong positive correlation
between the PI-umbilical and the ratio of the renal NIRS/cerebral NIRS on day 1 (ρ:
0.580). A positive correlation was also present between the PI-middle cerebral artery and
the ratio of the abdominal NIRS/cerebral NIRS measurements on day 3.
Conclusion: In IUGR infants, we demonstrated several associations between the fetal
bloodflow patterns before birth and the oxygenation of the various organs after birth. The
associations we found reflected brain sparing before birth which persisted up to 3 days
after birth. Ductus venosus flow patterns were associated with measures of general fetal
well-being. No associations were found between umbilical artery flow before birth and
tissue oxygenation of renal and abdominal organs.
4
Samenvatting
Achtergrond: intra-uteriene groei vertraagde (intrauterine growth restricted: IUGR)
foetussen hebben een groter mortaliteitsrisico en risico op het ontstaan van neonatale
morbiditeiten. IUGR leidt vaak tot redistributie van de foetale circulatie. De bloedstroom
naar de hersenen blijft relatief gespaard, terwijl die naar de abdominale organen verminderd
is. Het is nog niet bekend hoe deze circulatiedistributie veranderd na de geboorte in IUGR
kinderen.
Doel: het bepalen van de relatie tussen de echo Doppler metingen in IUGR foetussen en de
distributie van de circulatie in IUGR kinderen tot drie dagen na de geboorte.
Methode: Wij hebben tussen mei 2012 en juli 2013 prospectief IUGR kinderen
geïncludeerd, van wie de moeders onder controle waren vanwege verdenking IUGR bij de
afdeling Obstretrie en Gynaecologie in het UMCG. Inclusiecriteria waren een
zwangerschapsduur tot 42 weken en foetussen met een abdominale omtrek <10e percentiel.
We excludeerden foetussen en kinderen met chromosomale abnormaliteiten, syndromen en
congenitale infecties. Vanaf het moment dat IUGR was gediagnosticeerd, deden we
wekelijks echo Doppler metingen en rekenden we de PI uit van de foetale arteria umbilicalis,
de arteria cerebri media en de ductus venosus. Direct na de geboorte deden we dagelijks
NIRS metingen gedurende 2 uur continu op de eerste 3 dagen. Als uitkomstwaarden hebben
we de multisite NIRS waarden, i.c. rSO2, transcutane SO2 (SpO2), en de uitgerekende
fractionele zuurstofextractie van het weefsel (FTOE) in cerebraal, renaal en abdominaal
(splanchnisch) weefsel gebruikt. Daarnaast hebben we de rSO2- en FTOE-ratio’s tussen
verscheidene organen uitgerekend. Vervolgens hebben we correlatiecoëfficiënten tussen de
PI waarden van de laatste foetale metingen voor de geboorte en de postnatale NIRS waarden
inclusief de ratio’s uitgerekend met de Spearman’s rank order correlatie test.
Resultaten: We hebben 21 kinderen geïncludeerd met een zwangerschapsduur mediaan van
38 weken (interkwartiel range IQR: 37-39), een mediaan geboortegewicht van 2195 gram
(1925-2535) en een mediaan cerebrale omtrek van 31 cm (30-32). Alle kinderen hadden een
geboortegewicht <P10. Voor de geboorte, was de mediaan z-score van de PI arteria
umbilicalis 1.67 (IQR: 1.30-2.66), de mediaan z-score van de PI arteria cerebri media was -
0.48 (-1.51-0.66) en de mediaan z-score van de PI ductus venosus was 2.26 (0.81-5.91). Op
dag 1 waren 21 kinderen gemeten door de multisite NIRS, dit waren 19 kinderen op dag 2 en
16 kinderen op dag 3. We hebben verscheidende significante correlaties gevonden tussen de
prenatale echo Doppler metingen en de postnatale NIRS metingen, de meest sterkste waren
op dag 1 en 2. De PI ductus venosus correleerde sterk met de SpO2 op dag 1 (Spearman’s ρ:
0.635). De PI ductus venosus correleerde positief en matig sterk met de renale NIRS
metingen op dag 3 (ρ: 0.657). Wat betreft de ratio’s, vonden we enkel een sterke positieve
correlatie tussen de PI arteria umbilicalis en de ratio van de renale NIRS/cerebrale NIRS op
dag 1 (ρ: 0.580). Er was ook een positieve correlatie tussen de PI arteria cerebri media en de
ratio van de abdominale NIRS/cerebrale NIRS metingen op dag 3.
Conclusie: We hebben verscheidene associaties tussen de prenatale foetale
bloedstroompatronen en de postnatale oxygenatie van organen aangetoond in IUGR
kinderen. De gevonden associaties weerspiegelden brainspairing voor de geboorte die
standhield tot 3 dagen na de geboorte. Stroompatronen van de ductus venosus waren
geassocieerd met maten van algemeen foetaal welzijn. Er zijn geen associaties gevonden
tussen de stroompatronen van de arteria umbilicalis en weefseloxygenatie van de renale en
abdominale organen.
5
Table of contents
Introduction
1.1 IUGR 6
1.2 Detection of IUGR 7
1.3 Doppler 7
1.4 Circulation 8
1.5 Near infrared spectroscopy 9
1.6 Multi-site near infrared spectroscopy 10
1.7 Aim 10
Methods
2.1 Design and patients 11
2.2 Ethical statement 11
2.3 Study procedures and parameters 11
2.4 Statistics 12
Results
3.1 Patient characteristics 13
3.2 Doppler ultrasound measurements and NIRS measurements 13
3.3 Spearman’s rank order Correlations 15
Discussion 19
Implications 22
Conclusion 22
References 23
6
1. Introduction
IUGR Intrauterine growth restriction (IUGR) represents a deviation from the expected growth
patterns. The decreased fetal growth associated with IUGR is an adaptation to
unfavorable intrauterine conditions that result in permanent alterations in metabolism,
growth and development (1). IUGR is used as a synonym for small for gestational age
(SGA); however these terms are not synonymous. It is possible that a fetus is consistently
small during the entire pregnancy without the decrease in fetal growth. This is also
defined as SGA. The cause of SGA may therefore be pathological, as in an infant with
IUGR, or non-pathological, such as a consistently small infant who is otherwise healthy.
IUGR can occur in all stages of the pregnancy. This means that IUGR occurs in both
preterm and full term born infants. The growth restriction can be equal in all of the fetal
parts, known as symmetric IUGR. The restriction can also be limited to the body of the
fetus and not to his head, whereby ‘brain sparing’ evolves, also known as asymmetric
IUGR.
To understand these clinical manifestations of IUGR, the pattern of normal growth has to
be known. Normal fetal growth represents the interaction between the genetically
predetermined growth potential and the health of the fetus, the placenta and the mother
(2). Normal fetal growth reflects a first phase of cell hyperplasia during the first 16 weeks
of gestation. Between 16 and 32 weeks, there is a second phase of both hyperplasia and
cell hypertrophy and involves increases in cell size and number. As from 32 weeks, there
is a phase of cellular hypertrophy with an immense increase in size of cells.
In case of symmetric IUGR, this is defined as a growth pattern in which all fetal organs
are decreased proportionally, in other words, a reduction in the intrinsic potential of fetal
growth. This reduction of growth is due to impairment of early fetal cellular hyperplasia
(2,3).
Asymmetric IUGR is characterized by a relatively greater decrease in abdominal size
than head circumference, i.e. brain sparing. This reduction of growth often occurs after
30-32 weeks, during the cell hypertrophy phase.
IUGR fetuses are considered to be an at risk population. In the Netherlands IUGR is one
of the major causes of perinatal death and infants born after IUGR have an increased risk
of morbidity in the early stages, such as sepsis, necrotizing enterocolitis (NEC),
intracranial hemorrhage, respiratory distress syndrome (RDS) and asphyxia (1,2). These
complications of IUGR most likely account for the prolonged hospitalization.
The causes of IUGR can be broadly classified as fetal, maternal and placental. Fetal
causes include chromosomal alterations, genetic syndromes, intrauterine infections and
inborn errors of metabolism. These fetuses progress mostly with early IUGR, which is
often severe. Maternal causes include clinical conditions like hypertensive disorders,
nutritional deficiencies, especially of vitamin C and E, the use of teratogenic substances,
and smoking, alcohol and drug abuse (4,5). Placental factors include an inadequate
placentation, which means that there is no destruction of the muscle and elastic portion of
the spiral arteries in the trophoblast migration which normally occurs between the 16th
and 18th
week of pregnancy. This inadequate placentation leads to a high resistance to
7
bloodflow and a decreased uterine-placental perfusion (6). Placental insufficiency is the
primary etiologic factor of asymmetric i.e. late IUGR.
Besides these causes of IUGR, a fetus can also be constitutionally small, i.e. parental
small length. In most cases, there are no complications associated with this type of
growth restriction (6). But it is still unknown whether there are consequences for a
constitutionally small fetus after birth.
Detection of IUGR
In order to diagnose IUGR it is essential to estimate gestational age accurately. A first
trimester ultrasound can date the pregnancy approximately. Measurements of a smaller
maternal fundal height relative to values expected for a given gestational age are among
the first sings to suspect IUGR (7). Ultrasound assessment of the fetus can eventually
exclude or confirm the diagnosis (8). To estimate the fetal weight, the ultrasound
measurements of the biparietal diameter (BPD), head circumference (HC), abdominal
circumference (AC) and femur length (FL) are required. IUGR is defined as abdominal
circumference of the fetus below the 10th
percentile. The ratios HC/AC and FL/AC are
useful to distinguish between the asymmetric and symmetric type of IUGR (9). Serial
ultrasound assessments are also important for the detection of congenital or syndromal
fetal abnormalities as a cause for IUGR.
A method of great value in the diagnosis and management of IUGR is the Doppler
ultrasound measurement (10). However; it is still difficult to make a distinction between
IUGR fetuses related to placental insufficiency and an infant being constitutionally small.
In other words, it is still a challenge to identify fetuses at risk.
Nowadays the health condition of a fetus at risk is estimated based on various
measurements: ultrasound measurements of biometry, amniotic fluid volume, doppler
blood flow profiles, fetal movements and cardiotocography. It is essential for the IUGR
fetus to stay in utero as long as possible, to decrease morbidity due to prematurity. The
risk of mortality and severe morbidity increases with a shorter gestational age. In case of
growth restriction, the circumstances in utero may be so appalling that the risk of injury
to the fetus increases if birth is postponed. For example, this injury can result in fetal or
neonatal death or impaired neurological development. Currently, it is still a dilemma
what the optimum time of birth will be in case of IUGR.
Doppler
Doppler ultrasound measurements may help to identify a compromised fetal circulation,
with high risk of mortality. Using the Doppler ultrasound, the pulsatily index (PI) of
various vessels can be determined, which is calculated as the peak systolic height of the
blood flow waveform minus the minimum diastolic height, divided by the mean
waveform height. Generally, a low pulsatility waveform is indicative of low distal
resistance and high pulsatility waveforms occur in high resistance vascular beds (11). By
determining the PI, Doppler ultrasound gives information about the bloodflow and is
thereby a sensitive screening method for placental IUGR (12). Doppler assessment of
IUGR evaluates two kinds of vessels:
- The arterial Doppler, which consists of the umbilical artery (UA) and the middle
cerebral artery (MCA). Doppler measurements of the UA evaluate the placental
vascular resistance and are correlated to placental insufficiency. Normally, the
8
resistance of the UA declines during pregnancy. In case of placental insufficiency,
the PI progressively increases. The cerebral artery Doppler, the main branch of
the circle of Willis, is used for the estimation of brainsparing. In case of brain
sparing, the PI of the MCA will decline during gestation.
- The venous Doppler, which consists of the ductus venosus (DV). This shunt
bypasses an amount of well-oxygenated blood from the umbilical vein and the
liver directly in the inferior vena cava. The waveform of the DV has two peaks:
an S peak during the ventricular systole and a D peak during the diastole.
Between these peaks there is a notch: the A notch, which represents the atrial
contraction. Abnormalities of the Doppler DV measurements concern several
situations like a decreased flow, a reversed A notch or an increased resistance.
Several studies have reported associations between these abnormalities and an
adverse perinatal outcome (13,14). In general, the venous Doppler gives
information about changes in the venous circulation of the fetus, which is
associated with an advanced stage of hypoxemia (10).
Circulation
It is already well known that the fetal circulation can be redistributed as a consequence of
IUGR (10). Especially in case of IUGR caused by placental insufficiency due to placental
vascular abnormality, a redistribution of the fetal circulation occurs. Luria et al. illustrate
that an increased placental resistance plays an important role in the preferential shift of
the cardiac output towards the brain (15). This redistribution of the cardiac output results
in an increased cerebral oxygen availability despite the reduction in total placental
oxygen delivery to the fetus. The study of Luria et al. shows a couple of mechanisms how
the fetus keeps the optimal distribution between the placenta and systemic circulation
(15). By measuring Doppler ultrasound in various fetal vessels, an estimation can be
made of the distribution of the fetal blood flow to the various organs. In a constitutional
small fetus we expect a relatively physiological distribution of the fetal circulation, and
thus relatively physiological Doppler ultrasound measurements. The transition of the
circulation between the fetal and neonatal period during delivery is well-known, which
involves the removal of the low-resistance circulation of the placenta, the reduction of
pulmonary arterial resistance and the onset of breathing, and finally the closure of the
three shunts (1). On the other hand, it is only partly known which changes in the
distribution of the neonatal circulation occur after birth. Especially in IUGR as a
consequence of placental pathology, we are not sure whether there will still be a
redistribution of the circulation of the infant. The distribution of the circulation in the
infant may be similar to the fetal circulation, except of course for the transitional changes
during delivery, but it also may change entirely due to the full availability of nutrients
and oxygen after birth. Therefore, we want to find out whether Doppler ultrasound
measurements before birth may indicate the distribution of the circulation of the infant
after birth. We expect, in case of a redistribution of the fetal circulation, that we will
observe consequences for the neonatal distribution of the circulation which may still be
redistributed.
9
Near infrared spectroscopy
The distribution of the circulation to various organs can be measured after birth by tissue
oxygen measurements, using near infrared spectroscopy (NIRS) (16,17). NIRS is a non-
invasive method which can be used to measure tissue oxygenation continuously. NIRS
has been introduced in 1977 by Jöbsis, as a manner to monitor cerebral oxygenation and
hemodynamics (18). NIRS is currently used as a clinical monitoring technique in
critically ill neonates admitted to the neonatal intensive care. The technique of NIRS
measurements is based on the transparency of biological tissue to light in the near
infrared part of the spectrum (700-1.000 nm). In comparison with visible light, this
covers the wavelength spectrum of 450-700 nm (20). Near infrared light is subsequently
absorbed by chromophores, consisting of oxygenated haemoglobin (O2 Hb),
deoxygenated haemoglobin (HHB) and cytochrome AA3 in the vessels which are within
the near infrared light beam (21).
The distinct absorption spectra of oxygenated and deoxygenated haemoglobin are shown
in figure 1. The absorption spectra of oxygenated and deoxygenated hemoglobin are
equivalent at 800 nm, also known as the isobestic point. Changes in absorption below and
above the isobestic point are used to determine the ratio of oxygenated and deoxygenated
hemoglobin. The NIRS spectrometer then calculates the ratio of oxygenated hemoglobin
to the total amount of hemoglobin, providing the absolute value: rSO2.
Fig. 1 At 800 nm, the absorption spectra of O2Hb and HHb is equivalent (isobestic
point), which is used to calculate hemoglobin concentration independent of
oxygen saturation (20).
The regional tissue oxygenation (rSO2) reflects a mixed vascular bed dominated by gas-
exchanging vessels. 75-85% of this vascular bed is venous. In fact, rSO2 contains
information about the oxygen demand (19). When arterial oxygenation (which is similar
to the transcutaneous saturation, SpO2) is measured simultaneously, the balance between
tissue oxygen supply and tissue oxygen consumption (fractional tissue oxygen extraction,
FTOE) can be calculated by using the following equation:
10
FTOE = (Sp02 – rSO2)/ SpO2 (21).
FTOE reflects the balance between oxygen supply and oxygen extraction and can be used
as an indicator for inadequate tissue oxygenation and perfusion (22).
Multi-site near infrared spectroscopy
A number of studies are known in which the rSO2 in different tissue beds is monitored in
addition to the brain. This method may more accurately represent total body perfusion in
neonates at risk of circulatory failure (23,24). Because of the presence of the cerebral
auto-regulation, cerebral blood flow and tissue oxygenation may be preserved during low
systemic blood flow. Somatic tissue oxygenation could give better information about the
organ perfusion (24).
Hanson et al. reported that bloodflow to the brain is under auto-regulatory control during
dehydration as the cerebral rSO2 remained unchanged during rehydration (25). On the
other hand, somatic tissue beds showed an increased oxygen extraction and a fall in the
rSO2 during dehydration and these tissue beds also showed an increase in rSO2 during
rehydration (25).
Multiple clinical and biochemical parameters of global tissue perfusion were correlated in
studies previously mentioned. Particularly lactate level is frequently used as a
biochemical marker to assess global tissue perfusion (26). Chakravarti et al. measured a
strong inverse relation between rSO2 values at the cerebral and renal sites and lactate
level (24). They also observed that the strength of the correlation between rSO2 and
lactate improves when rSO2 data from different sites are combined (27). Mittnach et al.
showed as well that combination of two ore more sites increased specificity, sensitivity,
and predictive value of NIRS-derived measurements in prediction blood lactate levels
(26).
Multi-site NIRS-derived data on early postnatal circulation might in particular be relevant
for IUGR infants. Especially in case of asymmetrical IUGR (i.e. brainsparing) measured
by Doppler ultrasound, multi-site NIRS-derived measurements are required for providing
better information about the distribution of the circulation after birth.
Aim In our study we focus on the detection of the placental dysfunction before birth and its
importance for the infant after birth. Our general aim was to determine whether Doppler
ultrasound measurements before birth may indicate the distribution of the circulation of
the infant after birth. The main question of our study was: Do the fetal bloodflow patterns
have an association with the oxygenation of the various organs after birth? To make this
question more specific, we monitor the oxygentation of several organs of the IUGR
infants in the first three days after birth, using multi-site NIRS. We monitored the
oxygenation of the brain, the perirenal zone and the intestines. The aim of this
observational study was to asses, in IUGR fetuses, the association between the PIs in
various fetal vessels measured by Doppler ultrasound before birth and the distribution of
the circulation in the infants in the first three days after birth.
11
2. Methods
Design and patients
We performed a prospective observational cohort study. We included IUGR infants
immediately after birth, of whom the mothers were monitored because of suspected
IUGR at the Department of Obstetrics and Gynaecology in the UMCG between May
2012 and July 2013. Inclusion criteria were all gestational ages up to of 42 weeks, and the
fetuses having an abdominal circumference below the 10th
percentile, measured with
ultrasound measurements of biometry. We included only singleton pregnancies. We
excluded fetuses and children with chromosomal abnormalities, syndromes and
congenital infections (toxoplasmosis or cytomegalovirus).
At time of diagnosis of (suspected) IUGR, which is before birth, we gave the parents
information about the study. We asked the final parental informed consent after birth.
Fetal and maternal data of pregnancy were obtained from the patients’ medical files.
Ethical statement
The protocol for this study was approved by our institutions’ ethical review board.
Written informal parental consent was obtained in all cases.
Study procedures and parameters
As determinants we used the prenatal Doppler ultrasound measurements. Doppler
ultrasound of the IUGR fetus is part of the standard patient care. Experienced employees
performed the examination with high-end echo systems at the Department of Perinatal
Diagnostics or the Department of Obstetrics and Gynecology of the UMCG. Using
Doppler ultrasound, PI of the fetal umbilical artery, middle cerebral artery and ductus
venosus was determined. We calculated the PI as the peak systolic height of the blood
flow waveform minus the minimum diastolic height, divided by the mean waveform
height.
From the moment of IUGR was diagnosed Doppler ultrasound measurements were
performed weekly. For this study we only included the last measurement of the PI of the
three vessels before birth. To correct for gestational age we calculated the z-scores of the
PI-measurements. These z-scores were used as our determinants. We also calculated the
ratio of the PI-middle cerebral artery and PI-umbilical artery to determine asymmetrical
IUGR.
Information of the subsequent course of pregnancy and delivery was collected from the
medical files of the patients: gestational age (GA), birth weight, caesarean section,
gender, pH of the umbilical cord, arterial pH, base excess, coiling index of the umbilical
cord, Apgar score and maternal factors as medication, parity, maternal age, BMI, diabetes
mellitus, hypertension, alcohol consumption, smoking and drug abuse during pregnancy.
We used an INVOS 5100C Near Infrared Spectrometer (Somanetics Corporation, Troy,
MI) to measure the regional tissue oxygenation (rSO2) of the brain, the left kidney and
the intestines of the infants after birth. We used paediatric and neonatal SomaSensors
(Somanetics Corporation). The neonatal SomaSensors were placed on the left
frontoparietal side of the infants’ head, the left posterior flank between T10 and L2, and
below the umbilicus to measure the cerebral, renal en intestinal i.e. splanchnic rS02,
12
correspondingly. We used specific bandages, Mepitel®, to avoid skin irritation and to
keep the Somasensor in place.
We also measured transcutaneous arterial oxygenation (SpO2), using pulse oximetry.
Next we calculated the FTOE by the follow equation: FTOE = (SpO2 – rSO2)/ SpO2.
We performed the multisite NIRS measurements in the first 3 days after birth, measuring
for two hours continuously on each day. The first measurements had to take place within
18 hours after birth. As outcome measures we used the multisite NIRS values, i.e. rSO2,
transcutaneous SO2 (SpO2), and the calculated FTOE in cerebral, renal and abdominal
(splanchnic) tissue. Additonally we calculated the rSO2- and FTOE-ratios between
several organs. We used the ratio of the rSO2 / FTOE of the cerebral and the renal region
as a measure of asymmetrical IUGR, i.e. brain sparing.
Statistics
In the statistical analyses, the Z-scores of the PI per vessel were shown as median and
interquartile range (IQR) and the tissue oxygenation as measured with NIRS: cerebral,
abdominal and renal rSO2 (median and IQR) and FTOE (median and IQR). We used the
prenatal Doppler ultrasound measurements as determinants which we describe as the Z-
scores of the PI per vessel. Both the rSO2 and FTOE values of the three arteries of the
infant were used as outcome variables. The ratio of both the rSO2 and FTOE of the
cerebral artery and the abdominal region and the ratio of the cerebral artery and the renal
artery were also used as an outcome measure.
To evaluate the association between the PI measurements before birth on one hand and
the FTOE measurements and FTOE ratio measurements after birth on the other hand, the
Spearman’s rank order correlation coeeficients were calculated. We used SPSS 20.0
(SPSS inc. Chicago, IL) for all statistical analyses. A p-value of <0.05 was considered
significant.
13
3. Results
Patient characteristics
Twenty-one infants were included in this prospective observational cohort study with a
median gestational age of 38 weeks (interquartile range IQR 37-39), a median birth
weight of 2195 grams (1925-2535) and a median cerebral circumference of 31 cm (30-
32). All infants had a birth weight percentile below the P10 and nine infants were
asymmetrical growth restricted. Six critical ill infants were admitted to the NICU of the
University Medical Center Groningen (UMCG). The median maternal age of the twenty-
one mothers was 28 years (26-33) and the median BMI was 20.7 (19.6-24.6). Eight out of
twenty-one mothers were smoking and four of these mothers quitted smoking during
pregnancy. One mother suffered from pre-eclampsia. Nine out of twenty-one were
vaginal deliveries; eleven women had a caesarian section. The characteristics of the 21
mothers and infants are shown in Table 1.
Table 1. Patient demographics. Data are expressed as median (interquartile range
IQR) or as absolute numbers (percentage). Abbreviations: GA gestational age; BW birth
weight; NICU neonatal intensive care unit.
Number 21
Male 10 (47.6%)
GA (weeks) 38.1 (37.3 – 39.0)
BW (grams) 2195 (1925 – 2535)
BW percentile 0-2,5 11 (57.1%)
BW z-score -2.00 (-2.00 to -1.75)
Head Circumference (cm) 31.0 (30.0 – 32.0)
Asymmetrical IUGR 9 (42.9%)
NICU admission 6 (28.6%)
Admission duration (days) 5 (4 – 8)
Apgar at 5 min 9.0 (8.0 -10.0)
Caesarian section 11 (52.4%)
Maternal age (yrs) 28.8 (25.9 – 32.9)
Maternal BMI 20.7 (19.6 – 24.6)
Maternal smoking 8 (38.1%)
Pre-eclampsia 1 (4.8%)
Doppler ultrasound measurements and NIRS measurements
For the Doppler measurements we only included the last measurements before birth. In
order to adjust for gestational age, we calculated z-scores of the PI measurements. We
included 21 women whereby a median z-score of the PI umbilical artery was 1.67
(interquartile range IQR: 1.30-2.66) was measured. We measured a median z-score of the
PI middle cerebral artery of -0.48 (-1.51-0.66), whereby one measurement could not be
executed due to fetal engagement. For the z-score of the PI ductus venosus we measured
14
Fig. 2 NIRS measurements on day 1, day 2 and day 3
a median of 2.26 (0.81-5.91), whereby three measurements were unfeasible due to
excessive fetal movements. Furthermore, we found a median z-score of the ratio of the PI
median cerebral artery and the PI umbilical of –0.31 (-0.82-0.39).
For the NIRS measurements we started the first measurement within 18 hours after birth
measuring for two hours continuously. Of the infants 21 had a multisite measurement on
day one, whereby two infants were missing the abdominal sensor due to extreme
prematurity. On day two 19 infants did undergo a multisite measurement due to discharge
of two infants. On day three, three more infants were discharged, thus 16 infants had a
multisite measurement. The medians and ranges of the cerebral NIRS-, the renal NIRS-
and the abdominal NIRS measurements on day 1 to day 3 are presented in Figure 1, as
box-whisker plots. The boxes represent the median and the interquartile range (IQR), the
whiskers represent the ranges of the measured values. Dots and stars represent outliers.
The medians and ranges of the calculated NIRS FTOE measurements per site on day 1 to
day 3 are presented in figure 2. FTOE we used as indicator for inadequate tissue
oxygenation and perfusion.
1 2 3
Day
15
Fig. 3 NIRS FTOE’s on day 1, day 2 and day 3
The renal NIRS measurements and the corresponding renal FTOE measurements on day
1 did differ from the measurements on day 2 and day 3. We found a wide range of the
abdominal NIRS measurements and the corresponding abdominal FTOE measurements
on day 1 to day 3.
Spearman’s rank order correlation coefficients
To evaluate the association between the PI measurements before birth on one hand and
the NIRS and FTOE measurements and NIRS and FTOE ratio measurements after birth
on the other hand, the Spearman’s rank order correlation coefficients were calculated. We
listed the several PI measurements and their correlations coefficients per day in Table 2,
Table 3 and Table 4.
We first measured the relationships of the PI-umbilical and the NIRS measurements, as
shown in Table 2. A signifant negative correlation between PI-umibilical and the ratio
renal NIRS/cerebral NIRS measurements was present on day 1, but not on day 2 and day
3. We found also a significant positive correlation between de PI-umbilical and the
corresponding ratio renal FTOE/cerebral FTOE measurements on day 1, but not on day 2
and day 3.
1 2 3
Day
16
Table 2. The relationships of PI-umbilical and NIRS-measurements.
DAY I ρ p-
value DAY II ρ
p-
value DAY III ρ
p-
value
rSO2cer 0,304 0,180 rSO2cer 0,218 0,371 rSO2cer 0,021 0,940
rSO2abd -0,102 0,679 rSO2abd 0,130 0,619 rSO2abd -0,358 0,208
rSO2ren -0,303 0,182 rSO2ren -0,091 0,710 rSO2ren -0,291 0,274
SpO2 -0,096 0,679 SpO2 -0,090 0,715 SpO2 -0,375 0,153
FTOEcer -0,366 0,103 FTOEcer -0,254 0,293 FTOEcer -0,129 0,633
FTOEabd 0,156 0,523 FTOEabd -0,150 0,567 FTOEabd 0,420 0,135
FTOEren 0,252 0,271 FTOEren 0,153 0,533 FTOEren 0,229 0,393
Ratio
rSO2ren/
rSO2cer
-0,447* 0,042
Ratio
rSO2ren/
rSO2cer
-0,326 0,173
Ratio
rSO2ren/
rSO2cer
-0,276 0,300
Ratio
rSO2abd/
rSO2cer
-0,237 0,329
Ratio
rSO2abd/
rSO2cer
0,064 0,808
Ratio
rSO2abd/
rSO2cer
-0,345 0,227
Ratio
FTOEren/
FTOEcer
0,436* 0,048
Ratio
FTOEren/
FTOEcer
0,342 0,152
Ratio
FTOEren/
FTOEcer
0,279 0,295
Ratio
FTOEabd/
FTOEcer
0,270 0,263
Ratio
FTOEabd/
FTOEcer
-0,125 0,633
Ratio
FTOEabd/
FTOEcer
0,336 0,240
* = correlation is significant at the 0.05 level (2-tailed)
** = correlation is significant at the 0.01 level (2-tailed)
The relationships between the PI-ductus venosus and the NIRS measurements per day are
shown in Table 3. Significant, strong positive correlations were present for
transcutaneous arterial oxygen saturation (SpO2) on day 1 and 2. The higher the PI in the
ductus venosus, the higher the SpO2. The abdominal rSO2 on day 1 and renal rSO2 on day
3 correlated also with PI-ductus venosus.
17
Table 3. The relationships of PI-ductus venosus and NIRS-measurements.
DAY I ρ
p-
valu
e
DAY II ρ
p-
valu
e
DAY III ρ
p-
valu
e
rSO2cer -0,135 0,593 rSO2cer 0,120 0,646 rSO2cer -0,090 0,759
rSO2abd 0,512* 0,043 rSO2abd 0,311 0,260 rSO2abd 0,077 0,812
rSO2ren 0,319 0,197 rSO2ren 0,184 0,480 rSO2ren 0,657* 0,011
SpO2 0,635** 0,005 SpO2 0,542
* 0,025 SpO2 0,216 0,459
FTOEcer 0,174 0,489 FTOEcer 0,074 0,779 FTOEcer 0,059 0,840
FTOEabd -0,397 0,128 FTOEabd -0,311 0,260 FTOEabd -0,042 0,897
FTOEren 0,011 0,964 FTOEren -0,083 0,751 FTOEren -
0,670*
*
0,009
Ratio
rSO2ren/
rSO2cer
0,011 0,964
Ratio
rSO2ren/
rSO2cer
0,386 0,147
Ratio
rSO2ren/
rSO2cer
0,631* 0,016
Ratio
rSO2abd/
rSO2cer
0,303 0,254
Ratio
rSO2abd/
rSO2cer
0,204 0,467
Ratio
rSO2abd/
rSO2cer
-0,042 0,897
Ratio
FTOEren/
FTOEcer
0,001 0,997
Ratio
FTOEren/
FTOEcer
-0,324 0,205
Ratio
FTOEren/
FTOEcer
-0,525 0,054
Ratio
FTOEabd
/
FTOEcer
-0,276 0,300
Ratio
FTOEabd
/
FTOEcer
-0,293 0,289
Ratio
FTOEabd
/
FTOEcer
0,021 0,948
* = correlation is significant at the 0.05 level (2-tailed)
** = correlation is significant at the 0.01 level (2-tailed)
The relationships between the PI-middle cerebral artery and the NIRS measurements per
day are shown in Table 4. Again, several correlations were found, in particular of
cerebral NIRS values (day 2 and 3) and cerebral / renal and cerebral abdominal ratios on
day 1 and 3. The lower the PI of the middle cerebral artery was, the higher the rSO2 was
in brain tissue, and the lower the cerebral FTOE was.
18
Table 4. The relationships of PI-middle cerebral artery and NIRS-measurements.
DAY I ρ p-
value DAY II ρ
p-
value DAY III ρ
p-
value
rSO2cer -0,392 0,087 rSO2cer -0,374 0,115 rSO2cer -
0,574* 0,020
rSO2abd 0,243 0,332 rSO2abd 0,088 0,736 rSO2abd 0,380 0,180
rSO2ren 0,314 0,178 rSO2ren -0,030 0,904 rSO2ren 0,129 0,633
SpO2 0,386 0,093 SpO2 0,089 0,718 SpO2 0,372 0,156
FTOEcer 0,418 0,067 FTOEcer 0,456* 0,050 FTOEcer 0,574* 0,020
FTOEabd -0,185 0,436 FTOEabd -0,115 0,660 FTOEabd -0,415 0,140
FTOEren -0,220 0,352 FTOEren 0,025 0,920 FTOEren -0,047 0,863
Ratio
rSO2ren/
rSO2cer
0,580** 0,007 Ratio
rSO2ren/
rSO2cer
0,451 0,053 Ratio
rSO2ren/
rSO2cer
0,456 0,076
Ratio
rSO2abd/
rSO2cer
0,352 0,152 Ratio
rSO2abd/
rSO2cer
0,221 0,395 Ratio
rSO2abd/
rSO2cer
0,626* 0,017
Ratio
FTOEren/
FTOEcer
-0,474* 0,035 Ratio
FTOEren/
FTOEcer
-0,418 0,075 Ratio
FTOEren/
FTOEcer
-0,300 0,259
Ratio
FTOEabd/
FTOEcer
-0,273 0,272 Ratio
FTOEabd/
FTOEcer
-0,245 0,343 Ratio
FTOEabd/
FTOEcer
-
0,626*
0,017
* = correlation is significant at the 0.05 level (2-tailed)
** = correlation is significant at the 0.01 level (2-tailed)
19
4. Discussion
In this study we demonstrated associations between the fetal bloodflow patterns and the
oxygenation of the various organs after birth in IUGR infants.
The most and strongest of these associations we found on day 1 and day 2, but also on
day 3. The strongest positive association we found between the PI-ductus venosus and the
transcutaneous oxygen saturation, on day 1 and 2, suggesting that ductus venosus flow
patterns were associated with measures of general fetal well-being. We found a negative
association between the PI-middle cerebri artery and cerebral NIRS measurements. These
associations reflected brain sparing before birth which apparently persisted up to 3 days
after birth. No associations were found between umbilical artery flow before birth and
tissue oxygenation of renal and abdominal organs. We found similar associations
between the NIRS measurements and the PI values and FTOE values and the same PI
values
A unexpected finding was that renal rSO2 values increased gradually from day 1 to day 3.
We also found a broad range of abdominal rSO2 and FTOE measurements on all three
days.
We found the strongest positive association between the PI-ductus venosus and the
transcutaneous oxygen saturation. The more the PI of the ductus venosus deviates
towards the right from the normal range, i.e. the higher the resistance of the vascular
beds, the better the transcutaneous oxygen saturation after birth becomes. This positive
significant association was only present on day 1 and day 2. The Society for Maternal-
Fetal Medicine Publications Committee reported that Doppler waveforms of the central
venous circulation reflects the physiologic status of the right ventricle and gives
information about the venous circulation of the fetus (28). This measurement helps to
indentify fetuses with suspected IUGR at an advanced stage of compromise (13,28).
Deviations of the flow in the ductus venosus is associated with increased perinatal
morbidity, fetal acidemia and perinatal and neonatal mortality (12). The prediction of
critical perinatal outcomes is improved when the venous qualitative waveform is
measured. Our data suggest that fetal compromise before birth, as reflected by an
increased PI of the ductus venosus, is related to relatively higher arterial oxygen
saturations during the first 2 days after birth.
It is already known that, in case of IUGR due to placental insufficiency, a redistribution
of the cardiac output occurs, which results in increased cerebral oxygen availability
despite the reduction in total placental oxygen delivery to the fetus. Organs sparing
effects take place at various levels and in a certain order of fetal compromise, in response
to deterioration of different parts of the fetal circulation. Bascchat et al. reported that
deterioration is progressive in the majority of the IUGR fetuses (12). Abnormal umbilical
artery Doppler precedes a decrease in the PI of the middle cerebral artery. Once
centralization of the circulation is established, deterioration with subsequent development
of late decelerations is associated with deviations of the ductus venosus pulsations (29,
30). Considering the fact that deviations in flow patterns of the ductus venosus are a late
event in the organ sparing effect, this indicates the importance of the oxygenation of the
fetal organs provided by the ductus venosus. We interpret the positive association
20
between the PI-ductus venosus and the trancutaneous oxygen saturation after birth as a
sort of compensation mechanism for the hypoxic state of the fetus, due to hypoperfusion.
This kind of compensation mechanism may result in a temporary hyperoxic state of the
infant after birth. Afterwards, the transcutaneous oxygen saturation may restore to
equilibrium in about 3 days. According to this interpretation, the ductus venosus appeared
to be an indicator of general fetal well being, which also may influence the state of well-
being of the infant after birth. This may support our hypothesis that a redistribution of the
circulation still exists for several days after birth.
As yet, it is not clear whether this compensation mechanism is part of a physiologic
adaptation to extra uterine life, or acts as a confounder. Kamlin et al. showed that healthy
newborn infants >31 weeks have a gradual rise in SpO2 during the first 5 minutes of life,
with a median SpO2 at 5 minutes of 90% (31). This adaptation mechanism of the oxygen
saturation immediately after birth is relatively rapid. Even though, it is not known if some
kind of equilibrium or adaptation occurs regarding the oxygen saturation during the first
few days after birth.
The absence of a positive correlation between the PI-ductus venosus and the
transcutaneous oxygen saturation on day 3 is hard to explain. We hypothesize that this is
part of an adaptation mechanism of the circulation in which the state of hypoperfusion
that existed before birth gradually declines after birth. It can also be explained by the
heterogeneity of the group of infants. Nevertheless, these explanations are highly
speculative and further research is necessary to investigate this accurately.
A particular finding was the declining renal RSO2 value from day 1 tot day 3. This may
be explained by the physiologic adaptation of the circulation of the kidney itself. Even so,
evidence lacks whether some kind of adaptation mechanism occurs in the circulation of
the kidney in newborns during the transition from fetal to extrauterine life. Guignard et
al. found that newborns have an high plasma creatinine which remains high for 1 to 2
weeks. Nevertheless, this type of adaptation is caused by disturbation of the intrauterine
maternal-fetal biochemical balance and not by a limitation of the perfusion of the kidney
(32). We hypothesize that some compensation mechanism influences the perfusion of the
kidney. A positive association between the PI-ductus venosus and the renal RSO2 was
present only on day 3. This may support the interpretation of the mechanism of
compensation from the intrauterine hypoxic state to a hyperoxic state directly after birth
and subsequently a declining RSO2 to equilibrium on day 3.
A negative association between the PI-middle cerebral artery and the cerebral NIRS was
present on day 3. This can be explained by the mechanism of brainsparing. This event is
caused by a lower resistance of the middle cerebral artery. The particular presentation on
day 3 may be explained by the heterogeneity of the group of growth restricted infants:
only the more severely ill infants with brainsparing still show the postnatal compensation
mechanism of the prenatal hypoperfusion on day 3.
We found some striking relationships between the ratio renal RSO2/cerebral RSO2, i.e.
brainsparing, and the PI-ductus venosus and the ratio renal RSO2/cerebral RSO2 and the
PI-middle cerebral artery. Only on day 1 we found a positive association between the PI-
21
middle cerebral artery and the degree of brainsparing, which we did not expect. The
higher the PI, the higher the resistance would be in the vascular beds (11), which
contradicted the phenomenon of brainsparing. This may be interpreted by the initially
intrauterine sparing effect of the middle cerebral artery in response to deterioration of
umbilical artery, which did compensate directly after birth by way of increasing
resistance of the middle cerebral artery.
We also observed an obvious positive relationship between the PI-ductus venosus and the
ratio renal RSO2/cerebral RSO2 on day 3. It is already known that Doppler ultrasound
measurements of the ductus venosus may help to predict the neonatal outcome (12).
These measurements are associated with neonatal mortality (37). A decrease in the PI-
middle cerebral artery precedes an aberrant PI-ductus venosus, which is a late event in
the redistribution of the circulation in IUGR infants. This means that only the more
severely ill infants showed this aberrant PI-ductus venosus measurements. The positive
relationship between the PI-ductus venosus and the degree of brain sparing on only day 3,
may be explained by the large variability in both the severity of the IUGR and the
variability in the degree of comorbidities of the group of infants. The variability in
gestational age of the infants can also be considered as an explanation. The median
duration of admission of the 21 infants was 5 days. Some of the less severely ill infants
were discharged after two days hospitalization and they did not have any NIRS
measurements on day 3. Only 16 infants had multisite NIRS measurements on day 3. A
number of the more severely ill infants had signs of brain sparing: 9 infants. We can
explain the positive relationship between the PI-ductus venosus and the degree of brain
sparing by the fact that only the more severely ill infants showed this association. Those
children had existing brain sparing and they had aberrant PI-ductus venosus
measurements. They subsequently showed a compensation mechanism for the
intrauterine hyperoxic state of the brain.
We hardly found significant relationships between the PI-umbilical artery and the NIRS
measurements. This finding was not in line with our hypothesis. A possible explanation
for the lack of significant associations is the fact that an increase of the PI-umbilical
artery is an early event in the redistribution of the circulation in IUGR infants. We
performed the Doppler ultrasound measurements weekly, but we only used the last
measurement before birth.
Finally, we found an association between the rSO2 values and the calculated FTOE
values. As mentioned earlier, rSO2 contains information about the oxygen demand. The
balance between tissue oxygen supply and tissue oxygen consumption (FTOE) can be
calculated when arterial oxygenation (tcSaO2) is measured simultaneously (21). Thereby
FTOE reflects the balance between oxygen supply and oxygen extraction and can be used
as an indicator for inadequate tissue oxygenation and perfusion (22). In our group of
infants the tcSaO2 values remained quite constant with a mean tcSaO2 of 97% from day 1
to day 3. This means that the rSO2 are associated with the FTOE values and that we only
did need to include the rSO2 values. This finding can be striking in the way of hypoxia:
rSO2 is an important measurement in the hypoxic hypoxia, whereas FTOE can be used as
an indicator for the ischemic hypoxia (33).
22
Our study has some limitations. First, a relatively small number of infants were included
in this study. This may have resulted in overlooking existing associations with potential
differences remaining undetected, whereas in a larger sample size this would not have
been the case. However, since we designed this study to be a prospective observational
cohort study and did not aim at providing answers but generating hypotheses instead, we
believe this design is adequate for this purpose. Second, we did not include a control
group in the study. This could have helped us by comparing the redistribution of the
circulation in the IUGR infants with the circulation in healthy infants. According to the
time-schedule, it was hard to manage the measurements in an additional control group.
The strength of this study is the longitudinal design of measurements we did in every
fetus and infant. Second, we included a group of ill infants that was varying in gestational
age, but was homogeneous qua origin of illness: placental dysfunction.
Implications
Our study may have several implications. First, our data indicate that hypoxia before
birth provoked a (over)compensation mechanism which results in a hyperoxia after birth.
This hyperoxygenation may have several adverse consequences. Ramani et al. found that
neonatal hyperoxia in a mouse model leads to abnormal neurobehavior, primarily deficits
in spatial and recognition memory, associated with smaller size of the hippocampus,
similar to findings in ex-preterm infants (34). It is currently known that IUGR infants
have an increased risk for cognitive impairment (35). Geva et al. showed that late-onset
IUGR compromises network functioning which influences the neuropsychological
outcomes of the infants (36). According to these findings we hypothesize that the
hyperoxia after birth may affect neuropsychological and cognitive outcomes of the
infants.
This leads to our second implication. The interpretations we made of the compensation
mechanisms of the circulation in IUGR infants could have consequences for the treatment
protocols immediately after birth, aiming at reducing hyperoxygenation. This is
particularly important for infants who need artificial respiration.
Finally, our findings indicate that the ductus venosus seems to be an indicator for the fetal
well-being and neonatal well-being. This may help to indicate the severity of the IUGR
and may eventually help in the timing of delivery.
Still, these implications are highly speculative and more research in a larger group of
infants is necessary to unravel the consequences of the redistribution of the circulation in
IUGR infants in more detail.
Conclusion
In IUGR infants, we demonstrated several associations between the fetal bloodflow
patterns before birth and the oxygenation of the various organs after birth. The
associations we found reflected brain sparing before birth which persisted up to 3 days
after birth. Ductus venosus flow patterns were associated with measures of general fetal
well-being. We explained most of these associations by compensation mechanisms. No
associations were found between umbilical artery flow before birth and tissue
oxygenation of renal and abdominal organs.
23
5. References
(1) Marcdante,K.J. Kliegman,R.M. Jenson,H.B. Behrman,R.E. editor. Nelson Essentials
of pediatrics. 6th ed. Philadelphia: Saunders Elsevier; 2009.
(2) Krishna U, Bhalerao S. Placental insufficiency and fetal growth restriction. J Obstet
Gynaecol India 2011 Oct;61(5):505-511.
(3) Nardozza LM, Araujo Junior E, Barbosa MM, Caetano AC, Lee DJ, Moron AF. Fetal
growth restriction: current knowledge to the general Obs/Gyn. Arch Gynecol Obstet 2012
Jul;286(1):1-13.
(4) Sato Y, Benirschke K, Marutsuka K, Yano Y, Hatakeyama K, Iwakiri T, et al.
Associations of intrauterine growth restriction with placental pathological factors,
maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.
Histol Histopathol 2013 Jan;28(1):127-132.
(5) Lieberman E, Gremy I, Lang JM, Cohen AP. Low birthweight at term and the timing
of fetal exposure to maternal smoking. Am J Public Health 1994 Jul;84(7):1127-1131.
(6) Robertson WB, Brosens I, Pijnenborg R, De Wolf F. The making of the placental bed.
Eur J Obstet Gynecol Reprod Biol 1984 Dec;18(5-6):255-266
(7) Belizan JM, Villar J, Nardin JC, Malamud J, De Vicurna LS. Diagnosis of
intrauterine growth retardation by a simple clinical method: measurement of uterine
height. Am J Obstet Gynecol 1978 Jul 15;131(6):643-646.
(8) Harding K, Evans S, Newnham J. Screening for the small fetus: a study of the relative
efficacies of ultrasound biometry and symphysiofundal height. Aust N Z J Obstet
Gynaecol 1995 May;35(2):160-164.
(9) Campbell S, Thoms A. Ultrasound measurement of the fetal head to abdomen
circumference ratio in the assessment of growth retardation. Br J Obstet Gynaecol 1977
Mar;84(3):165-174.
(10) Botsis D, Vrachnis N, Christodoulakos G. Doppler assessment of the intrauterine
growth-restricted fetus. Ann N Y Acad Sci 2006 Dec;1092:297-303.
(11) Keving Harrington SC editor. A Colour Atlas of Doppler Ultrasonography in
Obstetrics. London, Great Britain: Edward Arnold; 1995.
(12) Baschat AA, Gembruch U, Reiss I, Gortner L, Weiner CP, Harman CR. Relationship
between arterial and venous Doppler and perinatal outcome in fetal growth restriction.
Ultrasound Obstet Gynecol 2000 Oct;16(5):407-413.
24
(13) Bilardo CM, Wolf H, Stigter RH, Ville Y, Baez E, Visser GH, et al. Relationship
between monitoring parameters and perinatal outcome in severe, early intrauterine
growth restriction. Ultrasound Obstet Gynecol 2004 Feb;23(2):119-125.
(14) Figueras F, Martinez JM, Puerto B, Coll O, Cararach V, Vanrell JA. Contraction
stress test versus ductus venosus Doppler evaluation for the prediction of adverse
perinatal outcome in growth-restricted fetuses with non-reassuring non-stress test.
Ultrasound Obstet Gynecol 2003 Mar;21(3):250-255.
(15) Luria O, Bar J, Kovo M, Malinger G, Golan A, Barnea O. The role of blood flow
distribution in the regulation of cerebral oxygen availability in fetal growth restriction.
Med Eng Phys 2012 Apr;34(3):364-369.
(16) Brazy JE, Lewis DV, Mitnick MH, Jöbsis FF. Noninvasive monitoring of cerebral
oxygenation in preterm infants: preliminary observations. Pediatrics 1985;75:217.
(17) Wyatt JS, Cope M, Delpy DT et al. Quantification of cerebral oxygenation and
haemodynamics in sick newborn infants by near infrared spectrophotometry. Lancet
1986;2:1063-1066.
(18) Jobsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen
sufficiency and circulatory parameters. Science 1977 Dec 23;198(4323):1264-1267.
(19) Menke J, Voss U, Möller G, Jorch G. Reproducibility of cerebral near infrared
spectroscopy in neonates. Biol Neonate 2003;83:6-11.
(20) Pellicer A, Bravo Mdel C. Near-infrared spectroscopy: a methodology-focused
review. Semin Fetal Neonatal Med 2011 Feb;16(1):42-49.
(21) van Bel F, Lemmers P, Naulaers G. Monitoring neonatal regional cerebral oxygen
saturation in clinical practice: value and pitfalls. Neonatology 2008;94(4):237-244.
(22) Naulaers G, Meyns B, Miserez M, Leunens V, Van Huffel S, Casaer P, et al. Use of
tissue oxygenation index and fractional tissue oxygen extraction as non-invasive
parameters for cerebral oxygenation. A validation study in piglets. Neonatology
2007;92(2):120-126
(23) Fortune PM, Wagstaff M, Petros AJ. Cerebro-splanchnic oxygenation ratio (CSOR)
using near infrared spectroscopy may be able to predict splanchnic ischaemia in neonates.
Intensive Care Med 2001 Aug;27(8):1401-1407.
(24) Chakravarti SB, Mittnacht AJ, Katz JC, Nguyen K, Joashi U, Srivastava S. Multisite
near-infrared spectroscopy predicts elevated blood lactate level in children after cardiac
surgery. J Cardiothorac Vasc Anesth 2009 Oct;23(5):663-667.
25
(25) Hanson SJ, Berens RJ, Havens PL, Kim MK, Hoffman GM. Effect of volume
resuscitation on regional perfusion in dehydrated pediatric patients as measured by two-
site near-infrared spectroscopy. Pediatr Emerg Care 2009 Mar;25(3):150-153.
(26) Mittnacht AJ. Near infrared spectroscopy in children at high risk of low perfusion.
Curr Opin Anaesthesiol 2010 Jun;23(3):342-347.
(27) Hoffman GM, Ghanayem NS, Tweddell JS. Noninvasive assessment of cardiac
output. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2005:12-21.
(28) Society for Maternal-Fetal Medicine Publications Committee, Berkley E, Chauhan
SP, Abuhamad A. Doppler assessment of the fetus with intrauterine growth restriction.
Am J Obstet Gynecol 2012 Apr;206(4):300-308.
(29) Harrington K, Thompson MO, Carpenter RG, Nguyen M, Campbell S. Doppler fetal
circulation in pregnancies complicated by pre-eclampsia or delivery of a small for
gestational age baby: 2. Longitudinal analysis. Br J Obstet Gynaecol 1999
May;106(5):453-466.
(30) Arduini D, Rizzo G, Romanini C. Changes of pulsatility index from fetal vessels
preceding the onset of late decelerations in growth-retarded fetuses. Obstet Gynecol 1992
Apr;79(4):605-610.
(31) Kamlin CO, O'Donnell CP, Davis PG, Morley CJ. Oxygen saturation in healthy
infants immediately after birth. J Pediatr 2006 May;148(5):585-589.
(32) Guignard JP, Drukker A. Why do newborn infants have a high plasma creatinine?
Pediatrics 1999 Apr;103(4):e49.
(33) Kooi EM, van der Laan ME, Verhagen EA, Van Braeckel KN, Bos AF. Volume
expansion does not alter cerebral tissue oxygen extraction in preterm infants with clinical
signs of poor perfusion. Neonatology 2013;103(4):308-314.
(34) Ramani M, van Groen T, Kadish I, Bulger A, Ambalavanan N. Neurodevelopmental
impairment following neonatal hyperoxia in the mouse. Neurobiol Dis 2013 Feb;50:69-
75.
(35) Morsing E, Asard M, Ley D, Stjernqvist K, Marsal K. Cognitive function after
intrauterine growth restriction and very preterm birth. Pediatrics 2011 Apr;127(4):e874-
82.
(36) Geva R, Eshel R, Leitner Y, Valevski AF, Harel S. Neuropsychological outcome of
children with intrauterine growth restriction: a 9-year prospective study. Pediatrics 2006
Jul;118(1):91-100.
26
(37) Cosmo YC, Araujo Junior E, de Sa RA, de Carvalho PR, Mattar R, Lopes LM, et al.
Doppler velocimetry of ductus venous in preterm fetuses with brain sparing effect:
neonatal outcome. J Prenat Med 2012 Jul;6(3):40-46.
.
.