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Ultrasound Obstet Gynecol 2015; 46: 385–388
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.15664
Editorial
Fetal cerebral redistribution: a marker
of compromise regardless of fetal size
J. MORALES-ROSELLÓ*† and A. KHALIL‡
†Servicio de Obstetricia, Hospital Universitario y Politécnico La
Fe, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain;
‡Fetal Medicine Unit, St George’s Hospital, London, UK
*Correspondence. (e-mail: [email protected])
Stillbirth is both a tragedy for parents and traumatic
for the professionals involved in the care of the mother.
Incidence increases in the final weeks of pregnancy, in
parallel with that of late-onset fetal growth restriction
(FGR)1,2 , suggesting that the events are likely to be related.
Although many risk factors are associated with stillbirth3 ,
FGR as a result of placental insufficiency accounts for
half of all cases that occur in high-income countries4 . As
a result, screening for fetal compromise is performed with
ultrasound, comparing individual growth with population
centiles5 . However, this approach is unlikely to prevent
stillbirth occurring after 32 weeks’ gestation, as more than
half of these fetuses are not small in size6,7 .
FGR is also associated with a risk of neurocognitive
dysfunction2 . It is likely that stillbirth represents the
outcome of a pathological process, and that for every
fetal demise many more fetuses might theoretically be
affected by neurological impairment as a consequence
of mild hypoxia and suboptimal growth at term8 . Term
fetuses with a birth weight < 10th centile are more likely to
show brain abnormalities on magnetic resonance imaging
(MRI), in the form of under-development of the corpus
callosum and brain fissures9,10 . However, some studies
report that fetuses with signs of cerebral redistribution,
defined by a low middle cerebral artery (MCA) pulsatility
index (PI), might have a higher risk for abnormalities
such as lower communication and problem-solving
scores11 . In addition, term small-for-gestational-age
(SGA) fetuses with normal MCA-PI have been shown
to have similar neurodevelopmental outcome to that of
appropriate-for-gestational-age (AGA) fetuses, proving
the importance of fetal cerebral redistribution in the
etiology of adverse neurodevelopmental outcome11 . We
recently published new evidence supporting the role of
fetal cerebral redistribution in the identification of fetuses
that have failed to reach their growth potential12 . We, and
others, have demonstrated that, regardless of fetal size,
fetal redistribution is associated with a risk of adverse
pregnancy outcome13 – 21 . Here, we explain the rationale
for our proposed novel approach to the evaluation of fetal
wellbeing near term, in order to improve identification of
adverse outcome at term.
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Diagnosing failure to reach growth potential
Failure to reach growth potential has traditionally been
difficult to quantify, or even diagnose. Abnormal fetal
growth has conventionally been evaluated using arbitrary
thresholds of fetal size, commonly the 10th centile, using
either population or customized centiles22,23 . However,
this is a measure of abnormal fetal size rather than
FGR or failure to reach growth potential. SGA is used
commonly as a proxy to identify fetuses with abnormal
growth24,25 . However, the majority of SGA fetuses are not
pathologically growth restricted and do not demonstrate
signs of placental insufficiency. This is further confused
by the finding that a proportion of AGA infants also fail
to meet their growth potential or, more correctly, suffer
from occult placental insufficiency, and this population
contains the majority of stillbirths at term6,7,12,26 . In fact,
the proportion of AGA fetuses in pregnancies that result
in stillbirth has increased since the 1960s, from 55%
(1967–1976) to 77% (1999–2006), as demonstrated
in a population-based cohort study using data from
the Medical Birth Registry of Norway (1.9 million
singleton births at, or beyond, 37 weeks’ gestation during
1967 to 2006)27 . This observation suggests clearly that
efforts to reduce stillbirth have so far focused on SGA
fetuses, ignoring the AGA fetuses with occult placental
insufficiency.
Knowing the third-trimester growth potential of an
individual fetus would be useful to evaluate accurately
the degree of growth restriction and stratify the risk of
stillbirth and adverse perinatal outcome. However, previous attempts to define this growth potential have been
based mainly on second-trimester biometry extrapolated
to the third trimester, and did not gain popularity because
of mathematical complexity28 – 30 . Alternatively, growth
customization has succeeded allegedly in reducing the
stillbirth rate by adjusting centile curves for maternal
characteristics31 . However, this approach cannot define
fully the genetic potential of the individual fetus, but
merely places it on a centile that is more appropriate for
its own customized population. Despite such mathematical reallocation, it remains that the majority of perinatal
deaths and adverse outcomes at term, such as cerebral
palsy, occur in fetuses whose weight is well above the
10th centile7,32 – 35 . Therefore, fetal weight > 10th centile,
considered an appropriate weight at term, does not necessarily reflect fetal wellbeing and accordingly does not rule
out the risk of stillbirth in a fetus that may decompensate
once an apparently normal weight has been achieved.
The paradox of the growth-restricted AGA fetus
National guidance in the UK and the USA does not
recommend the use of fetal Doppler as a screening tool
EDITORIAL
Morales-Roselló and Khalil
386
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Perinatal mortality/1000 births
(b) 20
P < 0.0001
15
AGA
10
P < 0.0001
5
P < 0.001
P < 0.050
P = 0.241
10
<p
0
p1
to
25
5
p2
to
50
p5
0
to
75
90
0
to
(Figure 2). For this approach, fetal Doppler measurements
were used as an indirect measure of fetal wellbeing,
relying on the Doppler indices of blood flow redistribution in the fetus. Independently of fetal weight, we
used the cerebroplacental ratio (CPR), corrected for
gestational age and expressed in multiples of the median
(MoM), to define fetal compromise. CPR, defined as the
ratio between the MCA-PI and the umbilical artery PI
(UA-PI), has been shown to correlate better with adverse
outcome than do its individual components (MCA-PI
or UA-PI)37,38 . Using established population patterns of
perinatal risk, we applied a threshold at the 5th centile
of CPR-MoM of fetuses least likely to suffer from the
consequences of growth restriction (birth weight > 90th
centile). Accordingly, regardless of the fetal-weight centile, we propose that fetuses with CPR-MoM values below
this cut-off (< 5th centile) are considered at increased risk
of adverse pregnancy outcomes, secondary to late-onset
placental insufficiency or insult. Considering that the
majority of adverse outcomes, including stillbirth at term,
occur in fetuses of normal size, we studied AGA fetuses
with abnormal CPR. We observed that these fetuses were,
in fact, more prone to poor acid–base status at birth compared with those with normal CPR13,17,18 . Furthermore,
the frequency of operative delivery for presumed fetal
compromise was higher in AGA fetuses with low CPR
than in SGA fetuses with normal CPR, indicating that
CPR was more strongly associated with fetal compromise
as a result of placental insufficiency than was fetal size19 .
to
90
>p
5
The antenatal diagnosis of FGR using fetal biometry
alone has been challenged recently12,36 and an alternative
approach, based on fetal hemodynamics, to the weight
centile-based model was proposed by our group12,13,17 – 20
0
0
0
5
6
4
0
0
5
.7 7.7
<p <p1 <p1 <p2 <p5 <p8 <p8 <p9 <p9 97
9
p
o
o
o
o
o
o
o
o
<
≥p
t
t
t
t
t
t
t
t
.3 5
0 16
0 50 80 84 90
to
2
p
1
2
p
5
p
p
p
p
p
p
p
p9
BW centile
3
2.
<p
p7
A hemodynamic approach based on fetal
cerebroplacental ratio
(a) 12
11
10
9
8
7
6
5
4
3
2
1
0
Proportion of fetuses with FRGP
for placental insufficiency, except when the fetus is already
known to be SGA24,25 . Late-onset placental insult might
occur in fetuses that have already gained enough weight
to be considered AGA. However, the finding of fetal
hemodynamic changes in such a fetus might indicate that it
is suffering from FGR, despite the fact that its weight is still
above the 10th centile. Although estimated fetal weight
(EFW) tends to be below the 10th centile in the majority
of cases of early-onset growth restriction, in fetuses with
late-onset growth restriction, EFW appears to remain well
within the limits for AGA fetuses. As a consequence, a
small proportion of AGA fetuses, at any weight centile,
are at risk of stillbirth because they are growth restricted
(in the sense that their rate of growth is impaired, although
their absolute weight is still in the ‘normal’ range). This
concept is supported by the fact that the incidence of
stillbirth and perinatal mortality, stratified according to
birth-weight centiles, shows an increasing prevalence as
the centile falls below the 80th centile (Figure 1)7,33 . This
resembles the pattern and proportion of fetuses selected
by our novel approach using fetal cerebral blood flow
redistribution12 .
BW centile groups
Figure 1 (a) Perinatal mortality according to birth-weight centile
and timing of perinatal mortality ( , antepartum period; ,
intrapartum period; neonatal period) in fetuses delivered at or
after 37 weeks’ gestation in The Netherlands during the time period
2002–2008. (Figure reproduced from Vasak et al.7 .) (b) Proportion
of term fetuses with failure to reach growth potential (FRGP)
according to their birth-weight (BW) centile group (i.e. proportion
of fetuses with a cerebroplacental ratio (CPR) multiples of the
median (MoM) value below the established FRGP normality
threshold (CPR-MoM = 0.6765), which was calculated after
subtracting those cases with CPR-MoM < 5th centile observed in
the group with BW > 90th centile). Appropriate-for-gestational-age
(AGA) fetuses show a progressive decrease of CPR, which is
especially important in the group with BW < 25th centile. P-values
calculated using chi-square test plus Holm’s correction for multiple
comparisons. (Figure reproduced from Morales-Roselló et al.12 .)
Moreover, low CPR was associated with a higher risk of
admission to the neonatal unit (NNU) at term20 . Similar
results have been published by other groups, indicating
that fetuses with low CPR more frequently develop
fetal compromise in labor, are delivered by Cesarean
Ultrasound Obstet Gynecol 2015; 46: 385–388.
Editorial
387
be high, probably because adverse pregnancy outcomes,
such as intrapartum fetal compromise, aberrant umbilical
cord venous and arterial pH and admission to the NNU
are influenced largely by intrapartum confounders41 .
Whilst it might therefore be possible to postulate that the
hemodynamic model is ineffective, one could argue that it
represents a significant advantage over the reliance on fetal
weight, which has poorer performance than does CPR.
CPR-MoM
SGA (weight model)
P10
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
3
4
A model of fetal surveillance
0.6765 MoM
1
0
2
FRGP
(hemodynamic model)
10 20 30 40 50 60 70 80 90 100
Birth-weight centile
Figure 2 Scattergram showing the combined model of screening for
adverse outcome in late fetal growth restriction, according to
cerebroplacental ratio multiples of the median (CPR-MoM) and
birth-weight centile. Group 1, small-for-gestational-age (SGA)
fetuses with abnormal CPR. Group 2, appropriate-for-gestationalage (AGA) and large-for-gestational-age (LGA) fetuses with
abnormal CPR. Group 3, SGA fetuses with normal CPR. Group 4,
AGA and LGA fetuses with normal CPR. Our model identifies
Group 2 as fetuses with potential adverse outcome. These fetuses
were previously considered as normal fetuses. (Figure reproduced
from Morales-Roselló et al.13 .)
section for abnormal fetal heart-rate recordings and have
meconium-stained amniotic fluid14 – 16 . Furthermore, an
abnormal CPR at term predicts neurobehavioral problems
at 18 months of age, according to Internalizing and
Somatic Complaints scales, as demonstrated in the
Generation R Study (Rotterdam, The Netherlands,
2003–2007)39 . Our model identifies two groups of
fetuses at potential risk: fetuses with low birth-weight
centiles and fetuses with abnormal CPR-MoMs. In
addition, we demonstrated that this observation (the
link between cerebral redistribution and adverse fetal
outcome) was not exclusive of the MCA but also extended
to other cerebral vessels, such as the vertebral artery,
which develops from an entirely different embryological
origin18 . This similarity supports our proposal described
here. We have also demonstrated that EFW discordance
and CPR discordance are independent predictors of
the risk of perinatal loss in twin pregnancy, and that
their combination could identify the majority of twin
pregnancies at risk of perinatal loss40 .
The hemodynamic model compared with the weight
model
We have demonstrated that, compared with birth weight,
CPR is better associated with the need for operative
delivery for presumed fetal compromise, umbilical cord
venous and arterial pH at birth, and admission to the
NNU17,19,20 . It is important to emphasize that although
these associations exist, their predictive value is unlikely to
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Until now, it has been primarily small fetuses that
are considered at risk of adverse perinatal outcome2 .
However, as a large proportion of small fetuses do not
suffer from placental insufficiency, and a proportion
of AGA fetuses with low CPR may have chronic
hypoxia, we propose a combined assessment approach
for predicting adverse outcome using both EFW and CPR.
This approach might enable identification of the fetuses
with failure to reach their individual growth potential.
In a recent study we were able to demonstrate that
CPR combined with uterine artery Doppler and EFW,
recorded in the third trimester, could identify the majority
of pregnancies resulting in stillbirth and perinatal loss42 .
Furthermore, the model that combines hemodynamic and
weight parameters might provide a useful tool for further
research in order to evaluate possible markers of placental
insufficiency, and perform randomized clinical trials to
establish the appropriate management of term SGA
and AGA fetuses with abnormal Doppler and probably
placental insufficiency. Such a screening protocol has not
been investigated before.
It must be acknowledged that not all studies measuring
CPR at term compare with our results. In a recent
retrospective study43 , CPR was found to be a poor
predictor of adverse perinatal outcome. However, in
that study, SGA fetuses with low CPR were delivered
frequently by planned Cesarean section, leading to
underestimation of the predictive accuracy of CPR for
fetal distress in labor. Moreover, the prevalence of
stillbirth and birth asphyxia with low Apgar score and
low cord-blood pH may have decreased as a consequence
of earlier deliveries and, finally, CPR may have been
corrected for maternal and fetal characteristics, without
establishing whether these factors were involved in the
causal pathway for adverse outcome. These sources of
bias could theoretically lead to an underestimation of
the predictive accuracy of CPR for adverse perinatal
outcome.
A long way ahead through a more complex scenario
Management of the term fetus with growth restriction is
yet to be established as the pathophysiology of late-onset
growth restriction and the long-term consequences of
hypoxia have not yet been fully clarified44,45 . Although
our proposal adds complexity, in that some AGA fetuses
are growth restricted and at risk of adverse outcome, it
may provide an explanation as to why many stillbirth
Ultrasound Obstet Gynecol 2015; 46: 385–388.
388
cases at term are not small. Prospective studies are
needed to elucidate the best markers for diagnosis of
subtle hypoxia at term, the magnitude of the potential
neurological damage in AGA fetuses with abnormal CPR
and the best time to screen for adverse outcome in the third
trimester. Once these questions are answered, randomized
clinical trials will be required to determine the optimal
management of SGA fetuses and AGA fetuses with growth
restriction, once an appropriate diagnosis, according to
any of the indicated tests, has been performed.
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