Ultrasound Obstet Gynecol 2015; 46: 452–459
Published online 25 August 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14920
Risk of ultrasound-detected neonatal brain abnormalities
in intrauterine growth-restricted fetuses born between
28 and 34 weeks’ gestation: relationship with gestational age
at birth and fetal Doppler parameters
R. CRUZ-MARTINEZ*†, V. TENORIO*, N. PADILLA*, F. CRISPI*, F. FIGUERAS* and
E. GRATACOS*
*BCNatal – Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clinic and Hospital Sant Joan de Deu), IDIBAPS,
University of Barcelona and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain; †Fetal Medicine and Surgery
Research Unit, Children’s and Women’s Specialty Hospital of Queretaro and Unidad de Investigación en Neurodesarrollo ‘Dr. Augusto
Fernández Guardiola’, Instituto de Neurobiologı́a, Universidad Nacional Autónoma de México (UNAM) Campus Juriquilla, Queretaro,
Mexico
K E Y W O R D S: aortic isthmus; Doppler; ductus venosus; intrauterine growth restriction; middle cerebral artery; myocardial
performance index
ABSTRACT
Objective To estimate the value of gestational age at
birth and fetal Doppler parameters in predicting the
risk of neonatal cranial abnormalities in intrauterine
growth-restricted (IUGR) fetuses born between 28 and
34 weeks’ gestation.
Methods Fetal Doppler parameters including umbilical
artery (UA), middle cerebral artery (MCA), aortic isthmus,
ductus venosus and myocardial performance index were
evaluated in a cohort of 90 IUGR fetuses with abnormal
UA Doppler delivered between 28 and 34 weeks’ gestation
and in 90 control fetuses matched for gestational age.
The value of gestational age at birth and fetal Doppler
parameters in predicting the risk of ultrasound-detected
cranial abnormalities (CUA), including intraventricular
hemorrhage, periventricular leukomalacia and basal
ganglia lesions, was analyzed.
Results Overall, IUGR fetuses showed a significantly
higher incidence of CUA than did control fetuses (40.0%
vs 12.2%, respectively; P < 0.001). Within the IUGR
group, all predictive variables were associated individually
with the risk of CUA, but fetal Doppler parameters
rather than gestational age at birth were identified as
the best predictor. MCA Doppler distinguished two
groups with different degrees of risk of CUA (48.5%
vs 13.6%, respectively; P < 0.01). In the subgroup with
MCA vasodilation, presence of aortic isthmus retrograde
net blood flow, compared to antegrade flow, allowed
identification of a subgroup of cases with the highest risk
of CUA (66.7% vs 38.6%, respectively; P < 0.05).
Conclusion Evaluation of fetal Doppler parameters,
rather than gestational age at birth, allows identification
of IUGR preterm fetuses at risk of neonatal brain
abnormalities. Copyright © 2015 ISUOG. Published
by John Wiley & Sons Ltd.
INTRODUCTION
Fetuses with early-onset intrauterine growth restriction
(IUGR) resulting from severe placental insufficiency
are at increased risk of adverse early and long-term
neurological outcome1 . In addition to the known risks
of prematurity, chronic hypoxia also contributes to
the risk of ultrasound-detected cranial abnormalities
(CUA) such as intraventricular hemorrhage (IVH) and
periventricular leukomalacia (PVL)2,3 . CUA have a strong
association with later neurodevelopmental and visual
impairments4 – 9 and its prediction could improve the
management of early-onset IUGR. From a clinical point
of view, this information could be relevant particularly
for fetuses delivered after 28 weeks’ gestation when
mortality is normally low10 , and the predicted risk of
neonatal morbidity should constitute the main reason for
delivery. Previous large studies on IUGR fetuses suggest
that neurological outcome is associated largely with
gestational age at delivery10,11 , but these studies included
many cases delivered before 28 weeks, when mortality
Correspondence to: Dr E. Gratacos, Maternal-Fetal Medicine Department, Hospital Clinic, University of Barcelona, Sabino de Arana 1,
08028 Barcelona, Spain (e-mail: [email protected])
Accepted: 31 May 2015
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Abnormal Doppler in IUGR fetuses and neonatal brain abnormality
and morbidity are exceedingly high and the margin for
clinical decision-making is small. It is unknown whether,
for similar gestational-age ranges, particularly beyond
28 weeks, fetal Doppler parameters predict a higher risk of
poor neurological outcome. This information is important
in order to understand whether Doppler monitoring could
be used to provide adjunct information relevant to the
decision of delivering later than 28 weeks.
Different fetal Doppler parameters have been proposed
as promising predictors of neonatal outcome. The clinical standards for fetal surveillance and timely delivery
are the umbilical artery (UA) and ductus venosus (DV)12 ,
particularly the finding of absent/reversed end-diastolic
velocity (A/REDV) which has been associated independently with the presence of acidemia and increased risk
of perinatal death13 – 15 . However, there is conflicting evidence of their value in predicting neonatal neurological
morbidity11,16 – 18 . Middle cerebral artery (MCA) Doppler
is considered a surrogate for fetal hypoxemia19 , but its
value in predicting neurological damage in preterm IUGR
remains controversial20,21 . Other cardiovascular parameters such as aortic isthmus (AoI) flow and myocardial
performance index (MPI) have been suggested as candidates for fetal surveillance of IUGR fetuses. These
parameters seem to provide only modest additional clinical value in predicting mortality in early-onset IUGR
when DV Doppler has been used already22,23 . Preliminary evidence suggests that AoI flow shows an association with long-term neurological outcome24,25 while
no previous studies have evaluated the association of
MPI with neurological outcome. There are no studies
evaluating the combined value of the Doppler parameters mentioned above in the prediction of neurological
outcome.
In this study we aimed to evaluate the value of
gestational age at birth and fetal Doppler parameters
in predicting the risk of neonatal CUA in early-onset
IUGR fetuses born between 28 and 34 weeks’ gestation.
METHODS
This was a prospective study including a cohort of consecutive singleton fetuses with early-onset IUGR, defined
as an estimated fetal weight < 10th centile according
to local standards26 , abnormal UA Doppler (pulsatility index (PI) > 95th centile)27 and delivery between 28
and 34 weeks’ gestation. All pregnancies were dated by
first-trimester crown–rump length measurement28 . Exclusion criteria were: congenital malformations, chromosomal abnormalities, neonatal death and confirmed birth
weight ≥ 10th centile26 . Controls were selected during the
same study period and were defined as singleton fetuses
delivered preterm with neonatal birth weight between 10th
and 90th centile26 and without clinical signs of chorioamnionitis. Controls were matched individually to cases by
gestational age at delivery (± 1 week). The protocol was
approved by the hospital ethics committee and written
consent was obtained from all women involved (IRB
2009/4712).
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
453
In all IUGR fetuses, Doppler ultrasound examinations
were recorded every 48–72 h by one of two experienced
operators (R.C.-M. or F.F.) using a Voluson E8 (GE
Medical Systems, Zipf, Austria) ultrasound machine
equipped with a 6–2-MHz linear curved-array transducer.
Doppler recordings were performed in the absence of
fetal movement and during maternal voluntary suspended
breathing. Spectral Doppler parameters were acquired
automatically from three or more consecutive waveforms,
with the angle of insonation as close to 0◦ as possible.
A high-pass wall filter of 70 Hz was used to record
low flow velocities and avoid artifacts. Mechanical and
thermal indices were maintained below 1.
UA-PI was measured from a free-floating cord loop.
DV was obtained in a midsagittal or transverse section
of the fetal abdomen, positioning the Doppler gate at the
isthmic portion. MCA-PI was obtained in a transverse
view of the fetal head, at the level of origin from the circle
of Willis. AoI-PI was measured either in a sagittal view
of the fetal thorax, with clear visualization of the aortic
arch, placing the gate a few millimeters beyond the origin
of the left subclavian artery, or in a cross-sectional view
of the fetal thorax, at the level of the three vessels and
trachea view, placing the gate just before the convergence
of the AoI and the arterial duct29 . MPI was measured
as described previously by Hernandez-Andrade et al.30 .
In brief, in a cross-sectional view of the fetal thorax, in
an apical projection and at the level of the four-chamber
view of the heart, the Doppler sample volume was placed
to include both the lateral wall of the ascending aorta
and the mitral valve at which clicks corresponding to the
opening and closing of the two valves could be visualized
clearly. Images were recorded using a sample volume of
3 mm, gain level of 60, Doppler sweep velocity of 8,
with the E/A waveform always displayed as positive flow.
Isovolumetric contraction time (ICT), ejection time (ET)
and isovolumetric relaxation time (IRT) were calculated
using clicks of the mitral and aortic valves as landmarks
and MPI was calculated as (ICT + IRT)/ET.
All Doppler parameters were normalized by converting the measurements into Z-scores according to
published normal reference values and were considered as abnormal with confirmed values > 95th centile
(+ 1.65 Z-scores)27,31 – 33 . MCA vasodilation was defined
as MCA-PI values < 5th centile (– 1.65 Z-scores) in two
consecutive observations (24 h apart)34 . UA, AoI and DV
Doppler were qualitatively dichotomized into present or
A/REDV according to the presence or absence of diastolic blood flow. A/REDV in the UA was defined as the
absence of antegrade flow in both UAs, in more than 50%
of the cycles and persistent in at least two examinations
12 h apart. Using the criteria described for UA, AoI was
considered to be reversed in the presence of retrograde
net blood flow during diastole, and A/REDV in the DV
was defined as the absence of antegrade flow during atrial
contraction. In all cases, only the last examination within
1 week of delivery was included in the analysis.
Betamethasone was given in all cases for lung
maturation. Cases with pre-eclampsia (PE) were managed
Ultrasound Obstet Gynecol 2015; 46: 452–459.
454
Cruz-Martinez et al.
Characteristic
Maternal age (years)
Primiparous
Non-Caucasian
Smoker
1–19 cigarettes/day
≥ 20 cigarettes/day
Pre-eclampsia
Cesarean delivery
GA at birth (weeks)
Birth weight (g)
Birth-weight centile
5-min Apgar score < 7
Neonatal acidosis
Neonatal unit stay (days)
Controls
(n = 90)
IUGR
(n = 90)
32.3 ± 5.2
51 (56.7)
22 (24.4)
7 (7.8)
6 (6.7)
1 (1.1)
10 (11.1)
37 (41.1)
31.1 ± 12.4
1616 ± 477
43.3 ± 20.3
3 (3.3)
5 (5.6)
30.1 ± 21.8
32.2 ± 4.9
45 (50.0)
17 (18.9)
7 (7.8)
5 (5.6)
2 (2.2)
46 (51.1)
85 (94.4)
31.2 ± 2.4
1078 ± 365
4.2 ± 5.4
5 (5.6)
8 (8.9)
42.9 ± 22.8
P*
0.89
0.61
0.37
1.0
0.76
0.56
< 0.001
< 0.001
0.73
< 0.001
< 0.001
0.47
0.39
< 0.001
Data are given as mean ± SD or n (%). *Student’s t-test and paired
t-test or McNemar test for independent and paired samples,
respectively. GA, gestational age.
according to standard guidelines35,36 . Delivery was
indicated if any of the following criteria were present:
decelerative cardiotocography (at least six decreases of
> 30 beats in 60 min)37 ; REDV in the UA, A/REDV
in the DV or persistent abnormal biophysical profile
(less than six on two occasions 8 h apart)38 ; maternal
complications secondary to PE. Metabolic neonatal
acidosis was defined as the presence of UA pH < 7.15
and base excess > 12 mEq/L at birth39 .
Neonatal intracranial ultrasound examinations were
performed sequentially on days 3 and 14 after birth, and
at 40 weeks of corrected postnatal age. All scans were
performed by one of two experienced operators (V.T.
or N.P.) who were blinded to results concerning the
fetal Doppler parameters evaluated in this study. Images
were acquired using Siemens Sonoline Antares ultrasound
equipment (Siemens Medical Systems, Malvern, PA, USA)
with the P10-4 neonatal probe set at a frequency
of 7.5 MHz. The intracranial ultrasound examination
included five sagittal and six coronal plane images
taken from the anterior fontanel. Abnormal increased
echogenicity of the white matter was reported if the
affected region was almost as bright as the choroid
plexus, according to Van Wezel-Meijler et al.40 . These
echodensities were classified as transient periventricular
echodensities if they were present at 72 h but had
disappeared by 14 days41 . Diagnosis of PVL was based
on ultrasound examination at day 14 after delivery and
was scored according to the classification described by
de Vries et al.42 . IVH was classified according to the
criteria described by Volpe43 . Basal ganglia lesions (BGL)
were diagnosed when an echodensity or an echolucency
was seen at any time within the basal ganglia area.
The presence of IVH, PVL or BGL at any ultrasound
examination was defined as any CUA and those that
were present at 40 weeks of corrected postnatal age were
defined as late CUA.
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Table 2 Frequency of ultrasound-detected cranial abnormalities
(CUA) in singleton pregnancies complicated by intrauterine growth
restriction (IUGR) and normal controls matched for gestational age
Cranial abnormality
IVH
Grade I
Grade II
Grade III
Grade IV
Transient periventricular
echodensities
PVL
Grade I
Grade II
Grade III
Grade IV
Basal ganglia lesions
Any CUA
Late CUA
Controls
(n = 90)
IUGR
(n = 90)
P*
9 (10.0)
7 (7.8)
0
2 (2.2)
0
12 (13.3)
20 (22.2)
12 (13.3)
3 (3.3)
4 (4.4)
1 (1.1)
33 (36.7)
< 0.05
0.22
0.08
0.41
0.32
< 0.001
7 (7.8)
7 (7.8)
0
0
0
0
11 (12.2)
2 (2.2)
18 (20.0)
13 (14.4)
5 (5.6)
0
0
13 (14.4)
36 (40.0)
23 (25.6)
< 0.05
0.15
< 0.05
—
—
< 0.01
< 0.001
< 0.001
Data are given as n (%). Some fetuses had more than one type of
CUA. *Adjusted for gestational age at birth by logistic regression.
IVH, intraventricular hemorrhage; PVL, periventricular
leukomalacia.
Frequency of abnormality (%)
Table 1 Maternal and neonatal clinical characteristics of singleton
pregnancies complicated by intrauterine growth restriction (IUGR)
and normal controls matched for gestational age
60
*†
50
*
*†
40
*
30
*
20
*
10
0
BGL
PVL
IVH
Late CUA
Any CUA
Figure 1 Frequency of basal ganglia lesions (BGL), periventricular
leukomalacia (PVL), intraventricular hemorrhage (IVH), late
ultrasound-detected cranial abnormalities (CUA) and any CUA in
90 control fetuses and 90 fetuses with intrauterine growth
restriction (IUGR) classified according to gestational age (GA) at
birth. *P < 0.05 compared to controls. †P < 0.05 among IUGR
fetuses. , control (GA at birth, ≥ 30 weeks); , control (GA at
birth, < 30 weeks); , IUGR (GA at birth, ≥ 30 weeks); , IUGR
(GA at birth, < 30 weeks).
Statistical analysis
Student’s t- or paired Student’s t- and McNemar tests
were used to compare independent and paired data,
respectively. The association between gestational age
at birth and abnormalities in the studied fetal Doppler
parameters and the risk of CUA was analyzed by
multiple simple logistic regression (for independent data)
or conditional logistic regression (for paired data) using
the Statistical Package for Social Sciences 19.0 statistical
software (SPSS, IBM Corp., Armonk, NY, USA).
A predictive model for the occurrence of any and
late CUA was constructed using the Decision Tree
Analysis algorithm (SPSS 19.0) which provides clinically
comprehensive classification algorithms that allow their
use in profiling individual risk for a given patient. The
Ultrasound Obstet Gynecol 2015; 46: 452–459.
455
Abnormal Doppler in IUGR fetuses and neonatal brain abnormality
(a) 60
*†
*†
(b) 60
50
Frequency of abnormality (%)
Frequency of abnormality (%)
50
40
30
*
*
20
*
*
BGL
PVL
40
*†
30
*
*†
20
10
0
*†
*
BGL
PVL
IVH
(d) 50
BGL
PVL
IVH
Frequency of abnormality (%)
Frequency of abnormality (%)
(c) 50
*†
20
0
IVH
*†
30
10
10
0
40
40
*†
30
*
20
*
*
10
0
BGL
PVL
IVH
Figure 2 Frequency of basal ganglia lesions (BGL), periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH) in 90 control
fetuses and 90 fetuses with intrauterine growth restriction (IUGR), with or without: (a) abnormal ductus venosus (DV) ( , controls; ,
IUGR, normal DV; , IUGR, absent/reversed DV); (b) aortic isthmus (AoI) retrograde net blood flow ( , controls; , IUGR, antegrade AoI;
, IUGR, retrograde AoI); (c) middle cerebral artery (MCA) vasodilation ( , controls; , IUGR, normal MCA; , IUGR, MCA
vasodilation); (d) absent/reversed end-diastolic flow in the umbilical artery (UA) ( , controls; , IUGR, antegrade UA; , IUGR,
absent/reversed UA). *P < 0.05 compared to controls. †P < 0.05 among IUGR fetuses.
decision tree was developed using the Classification and
Regression Trees CHAID method (Quick, Unbiased and
Efficient Statistical Tree) which generates binary decision
trees with the P inset at 0.05 (Bonferroni-adjusted for
multiple comparisons) and a cut-off selected automatically
for all parameters included44 . The classification and
regression tree was constructed by splitting subsets of
the dataset using all predictor variables to create two
child nodes repeatedly. The best predictor was chosen
using a variety of impurity and diversity measures. For a
parsimonious model, the number of cases to be present
for a split must be > 5% of the sample. Thus, the stopping
rules for the iterative process were: the tree should have a
maximum of three levels; a minimum of 10 cases were to
be present for a split to be calculated; and any given split
should not generate a group with fewer than two cases.
This allowed sequential analysis of variables to predict
the risk of CUA.
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
RESULTS
A total of 96 IUGR fetuses delivered between 28 and
34 weeks’ gestation fulfilled the inclusion criteria and
were recruited consecutively. Among them, six cases
(two stillbirths and four neonatal deaths) were excluded,
leaving a total of 90 cases that were matched by
gestational age at birth with 90 controls, resulting in
a final population of 180 fetuses for analysis.
The proportion of IUGR fetuses with MCA vasodilation, increased MPI, A/REDV in the UA, AoI retrograde
net blood flow and A/REDV in the DV were 75.6%,
67.8%, 42.2%, 26.7% and 7.8%, respectively. The primary indications for delivery were abnormalities in DV
(n = 7), decelerative cardiotocography (n = 11), abnormal biophysical profile (n = 11), A/REDV in the UA
(n = 35) and maternal complications secondary to PE
(n = 26).
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Cruz-Martinez et al.
(a) 100
(b) 100
*†
80
*†
70
60
50
40
*
30
20
90
Frequency of abnormality (%)
Frequency of abnormality (%)
90
*
Late CUA
*†
60
50
40
*
30
20
0
Any CUA
*
Late CUA
Any CUA
(d)
60
*†
50
40
*†
30
20
10
0
Late CUA
Any CUA
Frequency of abnormality (%)
(c)
Frequency of abnormality (%)
*†
70
10
10
0
80
60
*
50
40
*
*
30
20
*
10
0
Late CUA
Any CUA
Figure 3 Frequency of late ultrasound-detected cranial abnormalities (CUA) and any CUA in 90 control fetuses and 90 fetuses with
intrauterine growth restriction (IUGR), with or without: (a) abnormal ductus venosus (DV) ( , controls; , IUGR, normal DV; , IUGR,
absent/reversed DV); (b) aortic isthmus (AoI) retrograde net blood flow ( , controls; , IUGR, antegrade AoI; , IUGR, retrograde AoI);
(c) middle cerebral artery (MCA) vasodilation ( , controls; , IUGR, normal MCA; , IUGR, MCA vasodilation); (d) absent/reversed
end-diastolic flow in the umbilical artery (UA) ( , controls; , IUGR, antegrade UA; , IUGR, absent/reversed UA). *P < 0.05 compared to
controls. †P < 0.05 among IUGR fetuses.
Table 1 shows maternal and neonatal clinical characteristics of the population. According to our matched design,
gestational age at delivery was similar between cases and
controls. When compared with controls, in all IUGR
fetuses there was a higher frequency of CUA (40.0% vs
12.2%, respectively; P < 0.001; Table 2). Among IUGR
fetuses, transient periventricular echodensities were the
most frequent CUA (36.7%), followed by IVH (22.2%),
PVL (20.0%) and BGL (14.4%). In 25.6% of the IUGR
group, neonatal CUA persisted until 40 weeks of corrected
postnatal age.
Gestational age at birth was correlated negatively with
the risk of each CUA for both cases and controls, but
decision tree analysis identified the highest risk in neonates
who were delivered < 30 weeks. Within the IUGR group,
in fetuses delivered < 30 weeks there was a significantly
higher frequency of IVH and late CUA than in those
delivered ≥ 30 weeks (Figure 1).
Figures 2 and 3 show the frequency of each neonatal
CUA among controls and IUGR fetuses, classified
according to presence or absence of each fetal Doppler
abnormality. Within the IUGR group, presence of MCA
vasodilation was associated significantly with a risk of
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
IVH and BGL, A/REDV in the DV with a risk of PVL and
IVH, and AoI retrograde net blood flow with a higher
risk of each CUA. A/REDV in the UA was associated
significantly only with a risk of IVH. IUGR fetuses with
increased or normal MPI had similar respective risks
of BGL (14.8% vs 13.8%; P = 0.86), PVL (19.7% vs
20.7%; P = 0.96), IVH (23.0% vs 20.7%; P = 0.61), any
CUA (41.0% vs 37.9%; P = 0.61) or late CUA (26.2%
vs 24.1%; P = 0.46). Table 3 shows the odds ratios of
each CUA according to gestational age at birth and each
fetal Doppler parameter, using controls as the reference
group.
Decision tree analysis (Figure 4) identified fetal Doppler
parameters rather than gestational age at birth as the
best predictor of either any or late CUA, profiling three
groups with increasing risks. MCA Doppler was selected
as the initial predictor, discriminating a group with the
lowest risk of any CUA (13.6% in IUGR fetuses with
normal MCA Doppler vs 48.5% in those with MCA
vasodilation; P < 0.01) and late CUA (9.1% with normal
MCA vs 30.9% with MCA vasodilation; P < 0.05). In
the subgroup with abnormal MCA Doppler, presence
of AoI retrograde net blood flow identified a subgroup
Ultrasound Obstet Gynecol 2015; 46: 452–459.
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Abnormal Doppler in IUGR fetuses and neonatal brain abnormality
Table 3 Odds ratios (OR) of ultrasound-detected cranial abnormalities (CUA) in 90 fetuses with intrauterine growth restriction, according
to gestational age (GA) at birth and fetal Doppler parameters, referenced against control group of normal fetuses
Dependent
variables
Intraventricular
hemorrhage
GA at birth < 30 weeks 6.00 (1.94–18.50)
AoI retrograde flow
4.82 (1.62–14.40)
MCA vasodilation
3.58 (1.48–8.63)
A/REDV in the UA
4.94 (1.89–12.94)
A/REDV in the DV
10.10 (1.89–53.95)
Increased MPI
2.97 (1.17–7.52)
Periventricular
leukomalacia
Basal ganglia
lesions
3.95 (1.11–14.10)
6.83 (2.18–21.40)
3.37 (1.29–8.84)
4.07 (1.41–11.77)
14.60 (2.66–79.90)
3.04 (1.11–8.29)
Any CUA
4.89 (0.65–37.02)
7.18 (2.44–21.10)
37.50 (4.27–328.70) 13.40 (4.61–39.00)
10.40 (2.26–47.86)
7.12 (3.18–15.90)
9.91 (1.94–50.56)
6.84 (2.77–16.92)
17.40 (1.93–154.40) 37.70 (4.08–348.90)
7.73 (1.60–37.29)
5.63 (2.44–12.99)
Late CUA
44.00 (8.42–229.80)
57.40 (11.20–293.60)
21.40 (4.72–96.90)
21.50 (4.49–103.10)
94.60 (10.60–846.60)
18.90 (4.06–88.50)
Data are given as OR (95% CI). A/REDV, absent/reversed end-diastolic velocity; AoI, aortic isthmus; DV, ductus venosus; MCA, middle
cerebral artery; MPI, myocardial performance index; UA, umbilical artery.
IUGR (n = 90)
Any CUA (40% (36/90))
Late CUA (25.6% (23/90))
MCA
Normal MCA-PI (n = 22)
Abnormal MCA-PI (n = 68)
Any CUA (13.6% (n = 3))
P = 0.003
Any CUA (48.5% (n = 33))
Late CUA (9.1% (n = 2))
P = 0.04
Late CUA (30.9% (n = 21))
AoI
AoI antegrade net
blood flow (n = 44)
AoI retrograde net
blood flow (n = 24)
Any CUA (38.6% (n = 17))
P = 0.03
Any CUA (66.7% (n = 16))
Late CUA (15.9% (n = 7))
P < 0.001
Late CUA (58.3% (n = 14))
Figure 4 Clinical algorithm for prediction of any ultrasound-detected cranial abnormalities (CUA) and late CUA in fetuses with intrauterine
growth restriction (IUGR). AoI, aortic isthmus; MCA, middle cerebral artery; PI, pulsatility index.
of cases with a significantly higher risk of any CUA
(66.7% vs 38.6% in IUGR fetuses with antegrade AoI;
P < 0.05) and late CUA (58.3% vs 15.9%, respectively;
P < 0.001). Detection and false-positive rates for any CUA
using MCA were 91.7% and 64.8% as compared to
44.4% and 14.8% using aortic isthmus. For late CUA,
the detection rate was 91.3% at a false-positive rate of
70.1% with MCA, and 60.9% at a false-positive rate of
14.9% with AoI.
DISCUSSION
Studies in recent decades have shown that gestational
age at birth is the major determinant of mortality
and adverse neurological outcome among fetuses with
early-onset IUGR. Thus, regardless of abnormal fetal
Doppler parameters, delivery before 28 weeks’ gestation
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
seems to be associated with exceedingly high rates of
mortality23,45 and neurological morbidity10 , irrespective
of management protocols. Beyond 28 weeks, mortality
declines abruptly but there is no specific information on
the prevalence of neurological morbidity and its associated
factors. In order to address this question, this study was
designed to include only fetuses born between 28 and
34 weeks’ gestation. We examined the value of gestational
age at birth and fetal Doppler parameters in predicting
neonatal CUA, which is considered a sentinel sign for later
neurological disability4 – 9 . Our study provides evidence
that fetal Doppler parameters are a stronger predictor of
CUA than is gestational age at birth in early-onset IUGR
neonates delivered between 28 and 34 weeks’ gestation.
The results of the study with respect to Doppler
indices in the UA and DV are in line with previous
literature. A/REDV in the UA is a surrogate sign for severe
Ultrasound Obstet Gynecol 2015; 46: 452–459.
458
placental dysfunction12 . In this study, UA Doppler as an
independent factor was associated with a significantly
higher risk of IVH, but not with PVL or BGL, in IUGR
fetuses. When integrated in the decision tree analysis, UA
Doppler did not provide additional value. These findings
are in line with previous research indicating that UA
Doppler has a modest predictive capacity for neurological
morbidity11,46,47 .
Longitudinal studies suggest that fetal Doppler parameters change progressively during fetal deterioration, which
might provide opportunities for their combined use in clinical algorithms48 – 50 . Thus, DV becomes abnormal at later
stages of fetal compromise. This index is now accepted
widely as the best parameter for prediction of perinatal death10,14,15,45 , but there are conflicting views on its
role in the prediction of neurological morbidity. Baschat
et al., in a recent large multicenter study including 604
early-onset IUGR fetuses, reported a relative risk (RR) of
1.3 for neonatal morbidity in fetuses with A/REDV in the
DV11 . In this study, DV showed an individual association
with a significantly higher risk of IVH and PVL but did
not provide any additional value when MCA and AoI
were included in the model.
Concerning brain Doppler, the multicenter study of
Baschat et al. reported an RR of 3.3 for neonatal morbidity in fetuses with abnormal MCA Doppler11 . Along
the same line, Meyberg-Solomayer et al.51 demonstrated
that the combined presence of abnormal UA with MCA
Doppler identified neonates with a 38% risk of neonatal ventriculomegaly. In keeping with this contention,
we and others demonstrated previously that early-onset
IUGR fetuses with MCA vasodilation52 and those with
AoI retrograde net blood flow24,25 have poorer neurodevelopmental capabilities.
This study confirms previous results, signifying the
value of fetal Doppler parameters in predicting the risk
of neurological morbidity. The findings demonstrate that
a combination of MCA and AoI had an additive effect
in predicting CUA, which is considered clinically as an
important contributor to the risk of neurodevelopmental
delay in cognitive function and attention capacity and in
visual impairment4 – 9 . Thus, the risk of CUA increased
from 14% when both parameters were normal to 67%
when both were abnormal. These data add to the body
of evidence that increased brain perfusion is not an
entirely protective mechanism. Of note, IUGR fetuses
with normal MCA Doppler were similarly at risk of CUA
when compared to normal preterm newborns, reflecting
its high negative predictive value.
From a clinical perspective, the prediction of neurological morbidity is a major challenge in modern obstetrics
and lays the basis for timely delivery and future preventive interventions. The results of this study suggest that
AoI Doppler might be useful to improve timely delivery beyond 28 weeks’ gestation. The data support that,
for the same gestational age, AoI Doppler constitutes a
strong predictor of neonatal brain abnormality. While
these results should be confirmed by long-term follow-up
studies, the findings support the future use of AoI Doppler
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Cruz-Martinez et al.
in clinical decision-making for early-onset IUGR fetuses
beyond 28 weeks’ gestation. Aside from the contribution
to clinical management, profiling a subgroup with the
highest neurological risk could provide clues for targeted
interventions. This may include selecting cases for which
further neuroimaging would be useful53 or those that
would benefit from closer follow-up and early individualized intervention, in view of the effectiveness shown
by these strategies on white matter development54 and
short-term neurobehavioral dysfunction55 – 57 .
The strengths of this study are inclusion of cases at a
well-defined gestational-age range and inclusion of most
available Doppler indices in an integrated manner. In
addition, MCA and AoI Doppler were not used as criteria
for elective delivery. Concerning potential limitations of
the study, it must be acknowledged that the sample size
might have prevented detection of true associations in
very small subgroups, particularly for predictors such as
absent/reversed atrial flow in the DV which were present
in a small subset of cases. We acknowledge that the clinical
feasibility of complex Doppler evaluation requires experience and formal training to ensure reliability. However,
there is enough evidence supporting the reproducibility of
all Doppler indices evaluated here, if acquired by experienced operators. Although the high false-positive rate
of individual Doppler parameters may limit the utility
of their predictive value, the incorporation of Doppler
parameters into our clinical algorithm decreased the
false-positive rate for late CUA from 70% to 15%.
In conclusion, our study offers new evidence demonstrating that beyond 28 weeks’ gestation early-onset
IUGR is associated with a considerable proportion of
CUA and that fetal Doppler is the main predictor of
neonatal brain abnormality. These results should be
further confirmed by other groups and complemented by
long-term follow-up studies.
ACKNOWLEDGMENTS
The study was supported by grants from the Fondo
de Investigación Sanitaria (PI/060347) (Spain), Cerebra
Foundation for the Brain Injured Child (Carmarthen,
Wales, UK) and Thrasher Research Fund (Salt Lake City,
USA). R.C.M. was supported by the Mexican National
Council for Science and Technology (CONACyT).
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