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Review

Neonatology 2015;108:269276 Received: March 22, 2015


Accepted after revision: July 7, 2015
DOI: 10.1159/000438451
Published online: August 29, 2015

Brain-Sparing in Intrauterine
Growth Restriction: Considerations
for the Neonatologist
EmilyCohen a,b WillemBaerts a FrankvanBel a

a
Department of Neonatology, Wilhelmina Childrens Hospital/Utrecht University Medical Centre, Utrecht,

The Netherlands; b The Ritchie Centre, Hudson Institute of Medical Research and Department of Paediatrics,

Monash University, Melbourne, Vic., Australia

Key Words Introduction


Intrauterine growth restriction Small for gestational age
Brain-sparing Cerebral circulation Intrauterine growth restriction (IUGR) is traditionally
and most commonly defined as a birth weight below the
10th percentile for gestational age on the appropriate
Abstract population growth curve. IUGR is most commonly
Intrauterine growth restriction (IUGR) is most commonly caused by placental insufficiency, in response to which
caused by placental insufficiency, in response to which the the fetus adapts its circulation to preserve oxygen and nu-
fetus adapts its circulation to preserve oxygen and nutrient trient supply to the brain (brain-sparing). The altered
supply to the brain (brain-sparing). Currently, little is known cerebral haemodynamics may persist after birth, which
about the postnatal course and consequences of this ante- would imply a different approach with regard to cerebral
natal adaptation of the cerebral circulation. The altered ce- monitoring and clinical management of IUGR preterm
rebral haemodynamics may persist after birth, which would neonates than their appropriately grown (AGA) peers.
imply a different approach with regard to cerebral monitor- This review discusses the cerebral circulatory adaptations
ing and clinical management of IUGR preterm neonates than of IUGR fetuses and appraises the available literature on
their appropriately grown peers. Few studies are available the postnatal consequences of this phenomenon.
with regard to this topic, and the small body of evidence
shows controversy. This review discusses the cerebral circu-
latory adaptations of IUGR fetuses and appraises the avail- Brain-Sparing in the Compromised Fetus
able literature on their postnatal cerebral circulation with
potential clinical consequences. 2015 S. Karger AG, Basel In the situation of chronic fetal hypoxaemia or nutri-
ent deprivation, the fetus redistributes its cardiac output
to maximise oxygen and nutrient supply to the brain
(brain-sparing). The fetal circulation is a parallel circuit
where the majority of the right ventricular output is
shunted through the ductus arteriosus to the descending
aorta, and the left ventricle mainly supplies the upper
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2015 S. Karger AG, Basel Emily Cohen, MD


16617800/15/10840269$39.50/0 The Ritchie Centre, Hudson Institute of Medical Research
2731 Wright Street
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E-Mail karger@karger.com
Clayton, VIC 3002 (Australia)
www.karger.com/neo
E-Mail emily.cohen@monash.edu
body and the brain. Vasoconstriction of peripheral vas- frequently and earlier than changes in the MCA [68].
cular beds leads to an increase of the right ventricular af- This is in line with the theory of hierarchical CBF redistri-
terload. In the case of placental insufficiency, raised pla- bution: initially protecting higher cognitive functions of
cental vascular resistance contributes to this increased the frontal lobes which are supplied by the anterior cere-
systemic resistance [1]. On the other hand, vasodilation bral artery, followed by more elementary brain regions
of the cerebral arteries causes a decrease in left ventricular such as the basal ganglia, which are supplied by the MCA.
afterload. These changes result in a preferential shift of A number of authors have proposed that the calcula-
the cardiac output in favour of the left ventricle, enhanc- tion of the cerebroplacental ratio (CPR) is of additional
ing blood supply towards the brain [2]. value to diagnose brain-sparing [916]. This ratio be-
tween the MCA and UA-PI or -RI can be decreased, while
Regional Rather than Global Redistribution the individual values remain within normal limits. Some
It is now believed that brain-sparing occurs regionally authors have indicated that the CPR has a higher sensitiv-
rather than globally throughout the brain. Hernandez- ity than the MCA alone to predict perinatal and neonatal
Andrade et al. [3] have shown by measuring fractional outcome [9, 11]. Of these studies, however, many showed
moving blood volume (FMBV) that cerebral blood flow that fetuses with an abnormal CPR were born more pre-
(CBF) in IUGR fetuses shows regional changes with pro- maturely [9, 10, 12], which may have confounded their
gression of fetal deterioration. They saw an initial increase results.
in frontal FMBV, followed by a decrease as fetal condition
worsened. Basal ganglia FMBV, on the other hand, showed Reversal of Compensatory Flow
a steady and significant increase with fetal deterioration. There have been reports of severely compromised
The cerebellum showed a similar trend of FMBV increase IUGR fetuses displaying a return of the MCA-PI towards
related to the severity of fetal compromise. An increase in normal values [1719]. This reversal of compensatory flow
cerebellar FMBV may also imply enhanced blood supply is thought to be a pre-terminal sign. In fact, in a report by
to the brainstem, as both are fed through the posterior ce- Konje et al. [17], 4 out of 8 fetuses that showed MCA nor-
rebral circulation. The results of their study suggest a hi- malisation were subsequent stillbirths, and the other 4 died
erarchical order in cerebral blood supply in case of chron- during the neonatal period. It is not fully understood as to
ic hypoxia. At earlier stages, higher cognitive functions of why this reversal of compensatory flow occurs, and the
the frontal lobes are protected; however, under chronic cause may be multifactorial. It has been proposed that
and more threatening circumstances the focus seems to chronic hyperperfusion of the fetal brain leads to cerebral
shift towards survival, protecting important structures oedema, compromising CBF [19]. A decrease in CBF may
such as the basal ganglia and the brainstem [3]. also be a result of fetal cardiac decompensation [17]. The-
oretically, this could be due to reduced cardiac output [17],
Detection of Brain-Sparing but is more likely to result from venous congestion. In sup-
Changes in CBF associated with brain-sparing can be port of this hypothesis, postmortem cerebral examination
detected by Doppler sonography. Cerebral vasodilation of an IUGR fetus that succumbed following normalisation
and thus lowered cerebral vascular resistance lead to in- of CBF revealed not only marked dilatation of the MCA,
creased end-diastolic flow velocity in the cerebral arteries. but also periventricular radial congestion [18]. Periven-
As a result, it is believed that cerebral vasodilation and in- tricular congestion is thought to be of venous origin re-
creased CBF can be detected by a decrease in the pulsatil- lated to congestion of the vein of Galen [20, 21]. Enhanced
ity index [PI; (peak systolic flow velocity end-diastolic blood flow in the vein of Galen, indicating increased ve-
flow velocity)/time averaged flow velocity] or resistance nous return due to brain-sparing, has been reported in
index [RI; (peak systolic flow velocity end-diastolic flow IUGR fetuses [22]. Under normal conditions blood flow
velocity)/peak systolic flow velocity] of the cerebral arter- within this vein does not show pulsations [23], but pulsa-
ies. The middle cerebral artery (MCA) is used as the gold tility has been described in pregnancies complicated by
standard and a MCA-PI below the 5th percentile is gener- hypertension and IUGR [22, 23]. These pulsations are
ally classified as abnormal [4]. As blood flow redistribu- thought to result from transmission of pressure waves
tion has been shown to occur in a regional manner [3], from the venous circulation [23], which in turn are be-
brain-sparing may be present before it can be detected by lieved to represent fetal heart failure [24]. In conclusion,
an abnormal MCA-PI [5]. Several studies have reported fetal heart failure may compromise venous cerebral re-
CBF changes in the anterior cerebral artery to occur more turn, which subsequently may compromise brain-sparing.
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DOI: 10.1159/000438451
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Potential Consequences of Prolonged Brain-Sparing regulation. These non-responders were also found to
have a higher risk of being delivered for fetal distress and
Brain-sparing is in essence a protective mechanism the interval between the Doppler examination and deliv-
under chronic hypoxaemia; however, prolonged brain- ery was shorter compared to the responders, indicating
sparing may lead to an altered structure and function of that they were more compromised [42]. Impaired vasore-
the cerebral vasculature. activity may also be another explanation as to why loss of
compensatory brain-sparing as described previously
Cerebrovascular Remodelling can eventually occur. The case illustrated by Fignon et al.
Signs of vascular remodelling of systemic arteries have [18] showed that the cerebral RI and the CPR ceased to
been found in both human and animal studies of IUGR show normal physiological fluctuations, indicative of the
[2534]. It is thought that this vascular remodelling pro- loss of vascular reactivity, before the RI and CPR eventu-
cess is caused by the systemic haemodynamic changes ally rose and compensation of flow was reversed. If im-
seen in IUGR, which alter shear stress and wall tension paired vasoreactivity persists after birth, it can compro-
[35]. It is therefore plausible that similar vascular wall mise cerebral autoregulation, which is an important mech-
changes occur in the cerebral vessels since brain-sparing anism to prevent cerebral hypo- and hyperperfusion.
has great impact on the cerebral haemodynamics. In fact,
increased incidence of stroke has been reported in adults
born with low birth weight [36]. Although low birth Postnatal Cerebral Circulation following
weight is related to other risk factors for stroke such as Brain-Sparing
hypertension [37], the association between low birth
weight and stroke was most pronounced for individuals Currently, little is known about the postnatal cerebral
with low birth weight and low placental weight in relation circulation of IUGR neonates. The small body of evidence
to head size [36]. The relative increased head size suggests available in the literature indicates that the altered cere-
that brain-sparing was present in these individuals and bral haemodynamics that exist before birth persist post-
may have made them more susceptible to the occurrence natally. Similarly to prenatal Doppler observations, lower
of stroke [38]. However, very little research has been con- PI and RI of the MCA and anterior cerebral artery have
ducted in this area. Animal models of pregnant sheep us- been found up to 4 days postnatal age, indicating persis-
ing high altitude as a means to induce fetal hypoxia have tent dilatation of the cerebral arteries [4345]. In agree-
demonstrated changes in vascular wall composition and ment with these findings, increased CBF as measured by
contractility [39]. It has been suggested that these vascular Xenon-133 has also been reported on the first day of life
adaptations to chronic hypoxia help preserve energy while [46]. Moreover, higher regional cerebral oxygen satura-
still maintaining basic contractile function [40]. Although tion and reduced cerebral oxygen extraction have been
remodelling may help preserve energy under detrimental reported within the first 24 h of birth [47]. All of these
intrauterine circumstances, the postnatal implications of cerebral haemodynamic parameters have shown normal-
these adaptations have not been well investigated. In fact, isation within a few days, indicating that the cerebral cir-
a recent study demonstrated compromised structural in- culatory differences are transitory [44, 46, 47].
tegrity and stability of the cerebral microvasculature in Several Doppler measurements for CBF velocity (in-
IUGR lambs, increasing the blood-brain barrier permea- cluding the peak systolic velocity and time-averaged max-
bility and their risk for cerebral haemorrhages [41]. imum velocity) have been used to investigate CBF in
IUGR, as flow velocity changes of the MCA have been
Loss of Cerebral Vasoreactivity shown to correlate well with changes in CBF [48]. Con-
Prolonged brain-sparing and vascular remodelling may trasting results, however, have been reported [45, 4951].
lead to reduced vascular wall function. Prenatal loss of va- Blood flow velocity is not only influenced by flow volume
soreactivity in IUGR has been suggested by a study where and vessel diameter, but also by other factors such as hae-
human IUGR fetuses with brain-sparing were exposed to matocrit and vessel wall elastic properties [52]. It is well
maternal hyperoxygenation. A subset of these fetuses did known that neonates who were exposed to chronic hyp-
not show the expected rise in cerebral resistance in re- oxia in utero can present with polycythaemia. Increased
sponse to the increased oxygen levels. The finding that haematocrit was also reported in some of the studies men-
these fetuses did not adjust their cerebral circulation to the tioned previously [46, 47, 49]. Moreover, changes in vessel
new situation is suggestive of impaired cerebrovascular wall composition could potentially occur in IUGR [39].
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These factors, in combination with various types of mea- cerebral vessels to prevent hypoperfusion and ischaemia.
surements for blood flow velocity, have most likely con- Autoregulation is thought to partially rely on a myogenic
founded the results and led to the discrepancies among the reflex, where smooth muscle cells in the arterioles con-
reports. It is important to note that these factors, espe- tract or dilate depending on the intravascular pressure
cially the higher blood viscosity and increased oxygen car- [65, 66]. Other factors that influence the regulation of
rying capacity, could potentially confound all studies re- CBF include oxygen and carbon dioxide concentrations,
porting on cerebral haemodynamics and oxygenation, metabolic demand, and neuronal influences [65, 66].
which makes it difficult to interpret and compare results. The ability to autoregulate appears to increase with
gestational age. It is thought that autoregulation is im-
paired in sick preterm neonates, and it is believed that this
What Is Protected by Brain-Sparing? contributes to the ischaemic and haemorrhagic injury
frequently observed in this population [65]. As IUGR fe-
Thus far we have referred to brain-sparing as a protec- tuses are often delivered preterm, they are theoretically at
tive mechanism. It is important to note that recent research risk of impaired autoregulation. Due to vascular struc-
has challenged this conventional idea. Several studies in tural and functional changes, their autoregulation may be
both term and preterm populations have demonstrated further compromised and IUGR neonates may thus be
that IUGR subjects with brain-sparing show worse neuro- even less equipped than their AGA peers to cope with
developmental and behavioural outcomes than IUGR sub- hypo- and hypertensive circumstances. In contrast, Bauer
jects without signs of brain-sparing and controls [5358]. et al. [67, 68] found that low-birth-weight piglets exhib-
Although not all authors have confirmed this association ited a more adequate autoregulatory response to haemor-
[5961], these findings imply that brain-sparing may not rhagic hypotension and also higher brain oxygen extrac-
always protect against neurological damage [57]. Based on tion during hypercapnic hypoxia than their AGA peers.
these studies it has even been proposed that increased CBF These results suggest that chronic intrauterine hypoxia
reflects advancing stages of brain injury; not a protective may in fact stimulate the maturation of protective mech-
mechanism against it [54, 55, 57]. As described previously, anisms to ensure adequate brain oxygenation and perfu-
IUGR may be associated with vascular remodelling and sion. In this case, IUGR subjects may actually be able to
reduced vasoreactivity [18, 3942]. The increased CBF withstand periods of hypoperfusion and hypoxia better
may in part be a direct consequence of disturbed circula- than their AGA counterparts. It is important to note,
tory regulation. This theory is supported by the finding however, that these piglets were harvested from uncom-
that CBF remains elevated after birth, whilst the neonate is plicated pregnancies. Although asymmetric growth of
no longer exposed to a hypoxic environment and is no lon- these piglets does suggest that brain-sparing and thus a
ger in need of a compensatory increase in CBF [4347]. certain degree of intrauterine oxygen deprivation was
Hypothetically, postnatal continuation of increased CBF present, the haemodynamic disturbances and hypoxia
could cause hyperoxia within the fragile brain, which may may have been mild.
contribute to neurological damage [6264]. Despite its clinical significance, literature on this topic
It is of great clinical significance that the nature of the is extremely scarce and, to date, no studies have been per-
brain-sparing phenomenon is further investigated, as formed investigating cerebral autoregulation in human
new perspectives on this topic may have important impli- IUGR neonates.
cations for obstetric management of IUGR pregnancies.

Hypotension and Persistent Ductus Arteriosus


Cerebral Autoregulation
Hypotension and a haemodynamically significant per-
Autoregulation is the ability of the cerebral vasculature sistent ductus arteriosus (HSPDA) are both believed to
to maintain fairly constant CBF despite fluctuations in negatively influence CBF in AGA preterm infants [69,
cerebral perfusion pressure which are mainly affected by 70]. As discussed above, besides prematurity, cerebral
changes in systemic blood pressure [65, 66]. When sys- vascular wall changes could reduce vasoreactivity and
temic blood pressure increases, cerebral arterioles con- thus limit the autoregulatory response to protect the
strict to prevent hyperperfusion of the brain. A decrease IUGR brain against hypoperfusion under these circum-
in blood pressure is compensated for by dilation of the stances. Moreover, the autoregulatory response is limited
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DOI: 10.1159/000438451
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by the maximal dilation of the vessels [65]. In case of pro- severe peri-intraventricular haemorrhage show signs of
longed brain-sparing due to chronic hypoxaemia, maxi- cerebral hyperperfusion and suboptimal cerebral auto-
mal vessel dilatation may have already been reached, regulation. Thus, postnatal continuation of increased
which would further limit the protective response to hy- CBF [46, 47] in combination with potential loss of cere-
potension and HSPDA. Additionally, systemic vasocon- bral autoregulation [18, 65] and increased blood-brain
striction related to blood flow redistribution might still be barrier permeability [41] could make the preterm IUGR
in place, compromising the vasoconstrictor response to brain especially vulnerable to haemorrhagic insults. In
increase peripheral resistance in an attempt to raise blood fact, a sheep model of IUGR demonstrated highly re-
pressure. Furthermore, cardiac dysfunction has been re- duced perivascular astrocytes and pericyte coverage of
ported in IUGR neonates, which may also limit compen- the microvasculature in several brain regions, including
satory responses [32, 71]. For example, IUGR neonates the germinal matrix [41]. These histologic changes are
can present with diastolic dysfunction, restricting ven- believed to result in decreased stability of the cerebral mi-
tricular filling [32, 71]. The tachycardiac response to hy- crovasculature and are linked to ICH [41, 76]. Moreover,
potension would not be successful under these circum- IUGR neonates appear to have higher blood pressures
stances, as the increased heart rate would allow even less compared to their AGA peers [32, 33, 71], theoretically
time for already diminished ventricular filling, further further contributing to ICH risk.
compromising cardiac output [72]. Two recent studies have demonstrated a positive as-
In contrast, animal work by Bauer et al. [67, 68] has sociation between prenatal signs of brain-sparing and
suggested that exposure to chronic (mild) intrauterine ICH [77, 78]. In their large prospective study of 90 IUGR
hypoxia may actually improve autoregulation and cere- subjects, Cruz-Martinez et al. [77] found that IUGR neo-
bral oxygen extraction, allowing the IUGR brain to better nates with an abnormal prenatal MCA-PI presented with
withstand the effects of hypotension and HSPDA. It could ICH significantly more often than their non-brain-spar-
also be argued that postnatal persistence of increased CBF ing counterparts and controls. In the study by Ertan et al.
may reduce the impact of systemic hypotension or ductal [78], although prenatal Doppler data were available for
steal on the cerebral circulation. However, as postnatally only a subgroup of neonates, the MCA-RI appeared to be
increased CBF appears to be a temporary phenomenon lower in their ICH group. Contrastingly, others failed to
only lasting a few days, and vascular functional and struc- demonstrate an association between brain-sparing and
tural abnormalities may persist, protection against cere- ICH. Although gestational age differences may have con-
bral hypoperfusion may not be guaranteed beyond this founded the results of several studies reporting on this
period. Despite its clinical importance, we have little un- topic [7981], two studies in which gestational age was
derstanding of the impact of presumed hypotension and accounted for found no correlation between brain-spar-
HSPDA on the postnatal haemodynamics of IUGR redis- ing and ICH [82, 83]. According to these studies, brain-
tributing neonates. It is of major clinical importance that sparing does not increase the risk of haemorrhagic brain
these topics are addressed in future studies, as results may lesions. One study even found a reduced risk of ICH when
have a significant impact on neonatal management, espe- the MCA-PI was decreased [84]. Some authors have
cially since HSPDA appears to occur more frequently and therefore proposed that the adaptations to chronic in ute-
at an earlier time point in IUGR neonates compared to ro hypoxia may have accelerated maturation of autoregu-
their AGA peers [73] and the HSPDA diameter has also latory mechanisms, thus protecting against ICH [85].
been found to be larger in IUGR neonates [73]. It is un- The underlying pathology to ICH appears to be com-
clear why the occurrence and size of HSPDA is increased plex and multifactorial, but it has been proposed that ICH
in IUGR, but it may be related to vascular wall changes occurs after a period of cerebral hypoperfusion with sub-
which have been observed on histology of the ductus ar- sequent reperfusion [86, 87]. Hypothetically, increased
teriosus in this population [74]. cardiac output and brain-sparing in IUGR may prevent
cerebral hypoperfusion and protect the IUGR neonate
against ICH. As discussed previously, however, brain-
Intracranial Haemorrhage sparing may not be a (fully) protective mechanism. Hae-
modynamic instability and vascular remodelling may oc-
Intracranial haemorrhage (ICH) is a common compli- cur with long-standing or severe IUGR, which could im-
cation related to prematurity. A study by Alderliesten et pose a risk on the fragile preterm IUGR brain. Contrasting
al. [75] has shown that preterm neonates who develop results from the studies mentioned previously may thus
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Postnatal Consequences of Intrauterine Neonatology 2015;108:269276 273


Brain-Sparing DOI: 10.1159/000438451
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not only be explained by technical differences (various peers, they form a separate group within the premature
definitions, methods and timing to detect brain-sparing NICU population. They will require a different approach
and ICH) or confounders (gestational age, influence of with regard to the interpretation of cerebral oxygenation
clinical management), but may also rely on the severity of measurements and may need their own reference curves.
IUGR and fetal compromise.
In conclusion, the current literature shows conflicting
results and cannot exclude negative consequences of brain- Conclusion
sparing on the fragile cerebral vasculature. It is of great
clinical importance that this topic is explored further. Chronic intrauterine hypoxia and prenatal haemody-
namic disturbances appear to cause structural and func-
tional changes in the cerebral circulation. These intra-
Cerebral Oxygenation to Guide Clinical Management uterine adaptations appear to persist postnatally, and the
cerebral circulation of IUGR neonates is thus different
Although hypo- and hypertension are thought to be from their AGA peers during at least the first few days of
harmful for the preterm brain, the actual blood pressure life. However, the literature on this topic is extremely
range that ensures adequate brain perfusion is unknown scarce and the existing literature shows many controver-
[70]. Also, the absolute blood pressure values may not cor- sies. Therefore, the clinical consequences of these altered
relate with cerebral perfusion [88, 89]. Interestingly, cere- cerebral haemodynamics are poorly understood. It is thus
bral oxygenation has been shown to predict neurode- challenging to predict which fetuses are at greatest risk of
velopmental outcome better than the presence of hypo- adverse outcomes, and we currently have little under-
tension defined by absolute blood pressure values [90]. standing regarding the most appropriate cerebral moni-
Moreover, fluctuations of cerebral oxygenation and oxy- toring and management strategies for IUGR fetuses and
gen extraction have been related to the occurrence of ICH neonates. An international initiative addressing these is-
[75, 87]. It has therefore been proposed to consider mea- sues would be of great importance to improve the care for
surements of cerebral perfusion rather than absolute especially the preterm IUGR population.
blood pressure values as a basis for neonatal management
[88, 90]. Cerebral oxygenation indices as obtained with
Acknowledgment
near-infrared spectroscopy have been proposed as a useful
tool for routine clinical monitoring [90]. As IUGR neo- A scholarship was provided to Emily Cohen by SIDS and Kids
nates show different cerebral haemodynamics than AGA Australia.

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DOI: 10.1159/000438451
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