Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Antenatal tests of fetal wellbeing

Thomas R. Everett a, Donald M. Peebles b, *
a
Department of Fetal Medicine, University College London Hospitals NHS Foundation Trust, London, UK
b
Institute for Women's Health, University College London, London, UK

s u m m a r y
Keywords: In current obstetric practice, there is frequently a need to assess fetal wellbeing. This is particularly so in
Antenatal monitoring those fetuses at risk, including the small-for-gestational-age fetus or the fetus of a mother who presents
Umbilical artery Doppler
with reduced fetal movements or who has an obstetric complication such as pre-eclampsia. It is
Ductus venosus Doppler
Cardiotocography
important that the clinician is able to assess fetal wellbeing in such cases, especially in preterm gesta-
Short-term variability tions, when inappropriate delivery could have serious adverse consequences. In this paper, we review
the current evidence for the use and the limitations of widely used methods of antenatal monitoring
including the use of cardiotocography, biophysical profile, and ultrasound-derived parameters including
umbilical artery, middle cerebral artery, and ductus venosus Doppler flow.
© 2015 Elsevier Ltd. All rights reserved.

1. Introduction
In considering the most appropriate methods to assess the fetus
antenatally, it is worth considering the factors that lead to fetal
death or damage and the manner in which these present. The most
usual reasons to assess fetal wellbeing are small for gestational age,
either by ultrasound scan or by symphysis fundal height mea-
surement, or reduced fetal movements or signs/symptoms of
maternal/placental conditions that could affect the fetus such as
vaginal bleeding or pre-eclampsia. Whereas there are several
relatively rare causes of reduced fetal movement such as fetal
anemia related to feto-maternal haemorrhage or rhesus iso-
immunization, or a range of neurological conditions, the most
frequently occurring factor involved in all these scenarios is fetal
hypoxia. This can occur acutely, for instance as a result of placental
abruption, but more commonly from chronic deterioration of
placental function. The distinction is important, as the chronicity of
hypoxia has important implications for what is going to be the most
informative test.
The fetal response to acute hypoxia is well known and
described, mainly from studies in fetal sheep [1,2]. The cardiovas-
cular and metabolic responses are rapid in onset and include al-
terations in fetal heart rate, an increase in blood pressure,
redistribution of cardiac output away from the peripheries and
* Corresponding author. Address: Institute for Women's Health, University Col-
lege London, 74 Huntley St, London WC1E 6AU, UK. Tel.: þ44 (0) 207 679 6051, þ44
(0) 207 670 6051.
E-mail address: d.peebles@ucl.ac.uk (D.M. Peebles).
favoring the brain, heart, and adrenal glands, as well as a decrease
in fetal movements. The easiest of these acute hypoxia-related re-
sponses to detect is the change in fetal heart rate, and this is the
principle underlying the use of fetal heart rate monitoring, espe-
cially in situations where acute hypoxia is the main concern, such
as in labor. However, fetal sheep studies also show that, if the
hypoxic challenge is maintained for hours or days, many of these
adaptions revert to baseline (i.e., the fetal heart rate normalizes)
and the fetus starts to move. Only the redistribution of cardiac
output persists with ongoing hypoxia. It is only as chronic fetal
hypoxia becomes more severe, and is associated with myocardial
dysfunction and fetal acidosis, that blood flow through the ductus
venosus is affected. There are subtle signs on fetal heart rate
monitoring, such as a reduction in short-term variability or loss of
accelerations and a reduction in fetal movements.
It is clear that antenatal assessment of fetal heart rate or fetal
movement is only going to be of limited value in assessing fetal
wellbeing. Critical to the detection and management of chronic
fetal hypoxia is careful risk assessment based on history of known
or previous placental dysfunction, medical conditions such as
antiphospholipid syndrome or hypertension, or problems in the
current pregnancy, such as pre-eclampsia or abnormal pregnancy-
associated plasma protein-A or human chorionic gonadotrophin
levels. The placenta and its two circulations can be directly inves-
tigated using ultrasound; in particular, Doppler-measured indices
reflecting flow in the umbilical artery are pivotal in identifying
placental problems. However, it is ultimately the fetal response to
the hypoxic challenge that is crucial to identify the cause and
decide on timing of delivery. Of these, the most fundamental is fetal

http://dx.doi.org/10.1016/j.siny.2015.03.011
1744-165X/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Everett TR, Peebles DM, Antenatal tests of fetal wellbeing, Seminars in Fetal & Neonatal Medicine (2015),
http://dx.doi.org/10.1016/j.siny.2015.03.011
2 T.R. Everett, D.M. Peebles / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6

growth, as this reliably reflects substrate availability over a longer
time period (days to weeks). This chapter will focus on the tests
that can be used, either in the situation of fetal growth restriction or
reduced fetal movement, to identify the hypoxic fetus and deter-
mine the appropriate management to avoid stillbirth or long-term
neurologic disability.
2. Cardiotocographic monitoring
Cardiotocography (CTG) or electronic fetal heart rate monitoring
(EFM) is now widely used in clinical practice. In labor, continuous
CTG monitoring has been shown to reduce neonatal seizures, but
no long-term differences (including cerebral palsy and mortality)
have been shown between fetuses monitored continuously and
those monitored intermittently [3]. However, some have argued
that reduction in neonatal seizures could result in a reduction of
long-term cognitive impairment [4], although this remains to be
proven.
There is a paucity of good-quality evidence regarding antenatal
CTG monitoring. A Cochrane meta-analysis [5], including 1636
women deemed to be high risk, found no benefit of antenatal CTG
monitoring; there was a trend towards increased adverse outcomes
[risk ratio (RR): 2.05; 95% confidence interval (CI): 0.95, 4.42] for
perinatal mortality. Indeed, the most recent Royal College of Ob-
stetricians and Gynaecologists guidance on management of the
SGA fetus states that “CTG should not be used as the only form of
surveillance in SGA fetuses” [6].
However, computerized CTG monitoring can provide assess-
ment of short-term variability (STV), which cannot be performed by
visual assessment alone. STV has been shown to correlate with the
fetal metabolic state, and significantly reduced STV is closely
associated with fetal acidemia [7e9]; computerized CTG has been
shown to reduce perinatal mortality compared to traditional CTG in
the high-risk population [RR: 0.20; 95% CI: 0.04, 0.88] [5], but not if
deaths from congenital anomalies were excluded [OR: 0.23; 95% CI:
0.04, 1.29]. This analysis was based on only two studies and was
underpowered to detect a difference between groups.
3. Biophysical profile
The biophysical profile (BPP) combines the use of CTG with the
ultrasound assessment of fetal movement, fetal tone, fetal breath-
ing movements, and amniotic fluid volume. Each parameter is
scored 0e2 points, with a maximum total score of 10. A normal
score (8) is reassuring and has a high negative predictive value
and is associated with a low stillbirth rate (0.8%) [10]. However,
concerns have been raised regarding the large number of high-risk
women who would need to be assessed to prevent a poor outcome
and also a high false-positive rate, up to 60% [11]. The test is time-
consuming and labor intensive, and a modified BPP (deepest pool of
amniotic fluid and CTG assessment) has been shown to have a
similar negative predictive value as a full BPP. A recent Cochrane
review concluded that there is insufficient evidence to support the
use of BPP in high-risk pregnancies [12]. The review also high-
lighted the increased risk of intervention (induction of labor and
cesarean section) in women in the BPP arms of two studies [13,14]
and the need to carefully assess the possible risks of increased
intervention against the paucity of evidence of benefit in fetal or
neonatal outcomes.
4. Umbilical artery Doppler
In the Doppler assessment of fetal wellbeing, the umbilical ar-
tery (UA) is the most easily measured parameter and is the main-
stay of assessment in small fetuses or those at risk of compromise
[15]. The umbilical artery Doppler assesses blood flow from the
fetus to the placenta. Simply, increased resistance in the placenta,
suggestive of poor function, results in reduced diastolic blood flow
velocities. Initially, this is determined quantitatively through
increasing pulsatility index (PI) values. As resistance further in-
creases, qualitative changes in the waveform become evident
(Fig. 1), resulting in intermittently absent end-diastolic flow (EDF),
progressing to persistently absent EDF and ultimately reversed EDF,
which represents obliteration of >70% of placental tertiary villi
[16e18]. Ideally, Doppler measurement of the umbilical artery flow
should be performed in a free-floating loop, as there are well-
documented changes in the measurement values throughout the
cord, with impedance being highest at the fetal end, where wave-
form changes may be evident, whereas PI values are normal at the
placental end.
The Doppler measurement of umbilical artery flow has repeat-
edly been shown not to be useful in a low-risk or unselected pop-
ulation [19,20]. A recent Cochrane review, including >14,000
women from 20 studies, compared the outcomes of low-risk
pregnancies with either routine ultrasound or no Doppler ultra-
sound. This failed to demonstrate a reduction in perinatal death or
serious neonatal morbidity in the Doppler group, nor were there
differences in the secondary outcomes including prematurity,
mode of delivery, neonatal resuscitation, or a 5 min Apgar score <7
[21].
By contrast, the use of Doppler assessment of the umbilical ar-
tery flow in fetuses with growth restriction or those at risk, such as
hypertensive pregnancies, has been shown to reduce perinatal
mortality and unnecessary obstetric intervention [22]. Further
meta-analyses, comparing the use of umbilical Doppler in high-risk
groups, has confirmed this. A recent Cochrane review, including 18

Fig. 1. Changes in umbilical artery waveforms. (a) Normal with positive end-diastolic flow (EDF); (b) Abnormal with absent EDF; (c) Abnormal with reversed EDF.

Please cite this article in press as: Everett TR, Peebles DM, Antenatal tests of fetal wellbeing, Seminars in Fetal & Neonatal Medicine (2015),
http://dx.doi.org/10.1016/j.siny.2015.03.011
 T.R. Everett, D.M. Peebles / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
studies and >10,000 pregnancies, demonstrated that women with
Doppler assessment had a significantly lower perinatal mortality
(1.2%) compared to those without Doppler studies (1.7%) [RR: 0.67;
95% CI: 0.46, 0.96]. Although the data for secondary outcomes
showed that there were fewer adverse outcomes in the Doppler
group, this did not reach statistical significance [21]. Interestingly,
there was a reduction in interventions, such as induction of labor
and cesarean delivery in the Doppler group. Importantly, though,
there is a lack of data on long-term neurologic development on the
babies in either group, and whereas the quality of data is described
as low, the most recent study suitable for inclusion is more than a
decade old.
5. Middle cerebral artery Doppler
The middle cerebral artery (MCA) Doppler is an important in-
dicator of fetal anemia [23]. MCA peak systolic velocity (PSV) is
most widely used in the monitoring of fetuses at risk of Rhesus
disease or anemia secondary to viral infections such as parvovirus
B19. However, if a raised PSV is detected in a woman without
antibodies or recent viral infection, fetal anemia secondary to
acute or chronic feto-maternal haemorrhage should be considered
and is especially concerning in the presence of CTG abnormalities
[24,25].
The role of the cerebral arteries and the changes that occur in
the vessels are important in relation to the concept of “brain
sparing” in the chronically or acutely hypoxic fetus. Although
debated, the concept of brain sparing involves redistribution of
blood by dilation of the cerebral vessels, thus increasing substrate
and oxygen supply to the brain in response to fetal chemoreceptor
or baroreceptor stimulation.
Because of its position and course, the MCA is the most readily
measurable of the fetal brain vessels and readings can be obtained
in the majority of cases. Ideally, measurements should be taken in
an axial plane with the thalami and sphenoid bone wings visible.
The angle of insonation should be as close to 0 as possible and the
pulsed-wave Doppler gate should be placed over the proximal third
of the MCA. Pressure on the fetal head can significantly affect
readings, and care should be taken to avoid unnecessary pressure
from the transducer.
The value of MCA Doppler in the prediction of adverse fetal
outcome and the assessment of the “at-risk” fetus has been
inconsistent. Some studies have suggested that assessment of the
MCA Doppler is a useful tool, whereas others have found poor
predictive value [26e29]. Recently, a meta-analysis of 35 eligible
studies including 4025 fetuses was performed [30]. It is worth
noting that even within the included studies the definition of SGA
varied, the timing of MCA recordings in relation to outcomes
differed, and the definition of abnormal MCA also varied, though
most used PI < 2 SD or PI < 5th centile.
This meta-analysis found that low MCA PI appears to be predic-
tive of impaired fetal wellbeing assessed by either acidosis
(pH < 7.20) at birth, positive likelihood ratio (LR) 2.04 (95% CI: 1.17,
3.56), negative LR 0.67 (0.46, 0.98) (although this finding is largely
biased by a single study in a high-risk population [31], 5 min Apgar
score <7 [positive LR: 1.65 (1.07, 2.52), negative LR: 0.59 (0.37, 0.92)],
or admission to a NICU [positive LR: 4.00 (2.16, 7.50), negative LR:
0.62 (0.47, 0.82)]. Abnormal MCA is also predictive of an overall
composite measure of adverse perinatal outcome [positive LR: 2.77
(1.93, 3.96), negative LR 0.58 (0.44, 0.69)] and perinatal mortality
[positive LR: 1.36 (1.10, 1.67), negative LR: 0.51 (0.29, 0.89)].
Although these findings suggest that there is an association
between abnormal MCA and adverse outcomes, the association is
weak. In clinical practice, MCA has limited predictive value for
compromised fetal or neonatal wellbeing.
Please cite this article in press as: Everett TR, Peebles DM, Antenatal tests of fetal wellbeing, Seminars in Fetal & Neonatal Medicine (2015),
http://dx.doi.org/10.1016/j.siny.2015.03.011
3
6. Cerebro:placental ratio
There is a normal physiologic response of MCA dilation in fe-
tuses exposed to acute or chronic hypoxia, resulting in a reduction
in fetal MCA PI. Frequently, though not universally, these are
associated with increasing impedance in the umbilical artery,
suggestive of increased resistance in the placenta. Whereas the
values obtained on measuring these Doppler parameters may be
within normal limits, it is possible that the fetus is compensating.
By using the ratio of the MCA:UA Doppler PI (the “cere-
bro:placental” or “cerebro:umbilical” ratio), it may be possible to
determine which fetuses are at risk, as those with a low cere-
bro:placenta ratio (C:P) may have failed to reach their growth po-
tential [32,33].
Studies of the predictive role of the C:P ratio [32,34] have shown
cesarean section rates for fetal compromise, defined by abnormal
CTG or by fetal blood sample pH 7.20, to be significantly higher in
those fetuses with low C:P < 10th percentile measured within 72 h
of delivery. Notably, Apgar scores and arterial pH (taken at time of
delivery) do not differ, nor is there evidence of adverse neonatal
outcomes in the groups with low C:P ratio in either study. However,
others have reported a correlation between appropriate-for-
gestational-age (AGA) term fetuses with low C:P ratio and lower
umbilical artery pH [35], although in absolute terms the difference
is small and the long-term clinical outcomes have yet to be studied.
Interestingly, in SGA babies, low C:P ratio did not correlate with
lower pH, suggesting that the nature of SGA leaves a fetus with
lower metabolic reserves and, independently of C:P ratio, the fe-
tuses have lower arterial pH at birth. Others [36] have also asso-
ciated low C:P (PI < 1) with adverse perinatal outcome in
intrauterine growth retardation (IUGR). However, it may be most
useful when UA PI is > 95th centile with a normal waveform, in
which situation a low C:P gives an OR for adverse perinatal
outcome of 11.7 (6.0, 22.9). This provides similar predictive value to
abnormal UA waveform alone [OR: 10.8 (3.8, 30.5)] compared to 6.9
(2.9, 16.5) for raised UA PI alone.
7. Ductus venosus Doppler
The ductus venosus (DV) is a fetal vessel connecting the intra-
abdominal portion of the umbilical vein to the left portion of the
inferior vena cava just below the diaphragm [37]. The function of
the ductus venosus is to shunt the oxygen and substrate-rich blood
coming from the placenta via the umbilical vein to the heart. The
DV diverts 25% of the blood to the heart, with the remainder being
distributed to the liver and joining the circulation via the hepatic
portal system.
The ductus venosus is a “trumpet-shaped” vessel, which, in
combination with the venous pressure gradient, increases the ve-
locity of blood flow several-fold. Although entering the heart via
the right atrium, the high velocity and direction of flow preferen-
tially directs this substrate and oxygen-rich blood to the left atrium,
and then via the left ventricle and aorta to the fetal heart and brain
[38,39].
Sonographically, the DV can be identified with the use of color-
mapping in either the mid-sagittal view or an oblique transverse
view through the upper abdomen [37]. It appears as a small vessel
with relatively high velocities and on pulsed-wave Doppler usually
has a triphasic venous waveform. The DV waveform is sensitive to
cardiac function, which in turn is adversely affected by chronic
severe decrease in substrate/oxygen availability. In response to
hypoxia, the DV becomes more dilated and there is reduced flow
during ventricular diastole, resulting in increased DV pulsatility
index for veins (PIV), followed by increasingly retrograde flow
during atrial systole, seen as absent or reversed a-wave.
4 T.R. Everett, D.M. Peebles / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
Fig. 2. Changes in ductus venosus waveforms. (a) Normal with positive a-wave; (b) Abnormal with a-wave reversal.
The utility of the DV waveform is primarily in the very prema-
ture fetus with IUGR, or in the preterm fetus with abnormal UA
waveforms. Reversal or absence of the DV a-wave (Fig. 2), partic-
ularly in combination with umbilical vein pulsations, has been
shown to be closely associated with a pH < 7.20 (65% sensitivity and
95% specificity) [40]. Similarly, these venous Doppler changes are
associated with an 11-fold increase in major adverse neonatal
outcomes and a doubling in neonatal mortality [41].
However, up to 30% of fetuses with these venous Doppler ab-
normalities are not acidemic. At the extremes of prematurity,
especially in fetuses with growth restriction, this presents a clinical
dilemma when making a decision regarding optimal timing of de-
livery. Until recently, the GRIT study [42] provided the best pro-
spective randomized data on outcomes related to timing of delivery
in severely growth-restricted fetuses. Based on an abnormal UA
waveform, it showed no differences in mortality or long-term
outcome [43] between fetuses allocated either to immediate or to
deferred delivery. However, the TRUFFLE study has provided clar-
ification of outcomes in the cases of IUGR prior to 32 weeks'
gestation. In cases where delivery was determined by increased DV
PIV or absent DV a-wave, perinatal mortality was 6% and 10%,
respectively. However, neurologic impairment at 2 years of age was
9% and 5%, respectively. In those for whom delivery timing was
based on reduced CTG STV, perinatal mortality and abnormal 2-
year outcomes were 7% and 15%, respectively. Although the out-
comes were not significantly different between the groups, the
study suggests that delivery based on late Doppler changes, rather
than on reduced CTG STV, may provide better long-term outcomes,
possibly at the expense of a small increase in perinatal mortality. [It
is important to note that in the total cohort, 72% of women became
hypertensive, 50% developed pre-eclampsia or HELLP syndrome
(hemolysis, elevated liver enzymes, low platelet count) and 17%
required magnesium sulfate.]
8. Changes in Doppler parameters
The traditional view of the changes in Doppler parameters was
that as placental function deteriorated there was a clearly defined
sequence of changes in Doppler findings with an initial increase in
umbilical artery impedance (followed by changes in the waveform:
absent EDF and then reversed EDF, although these are considered
late changes often occurring after abnormal venous Doppler
changes). As placental function deteriorated further, the reduction
in oxygen and substrate to the fetus resulted in brain sparing and
reduction in the middle cerebral artery impedance. Changes in the
ductus venosus, initially with increased PIV and then reversal of the
a-wave, are later signs, as the fetal myocardium becomes increas-
ingly hypoxic and functions suboptimally [44].
Please cite this article in press as: Everett TR, Peebles DM, Antenatal tests of fetal wellbeing, Seminars in Fetal & Neonatal Medicine (2015),
http://dx.doi.org/10.1016/j.siny.2015.03.011
The recent PORTO study [45] has challenged this viewpoint. This
prospective study of 1116 fetuses with EFW <10th centile demon-
strated that there is no single predominant pattern of Doppler
changes. Nearly half (46%) of fetuses showed changes initially in the
umbilical artery with PI > 95th centile or absent or reversed EDF,
27% had MCA PI < 5th centile, and 11% had abnormal DV (either PIV
>95th centile, or absent or reversed a-wave.)
The pattern of adverse outcomes, such as intraventricular
hemorrhage, periventricular leukomalacia, hypoxiceischemic en-
cephalopathy, necrotizing enterocolitis, bronchopulmonary
dysplasia, sepsis, and death is also of interest. Eighty-six percent of
fetuses with abnormal UA had adverse outcomes, compared to 51%
with abnormal MCA and only 25% with abnormal DV Doppler. By
contrast with the TRUFFLE study, this study included late preterm
gestations, up to 36þ6 weeks' gestation. In the PORTO study, timing
of delivery was at the discretion of the lead clinician, and fetuses
with absent EDF in the UA were, by consensus, delivered at 34
weeks' gestation, by contrast with 32 weeks in the TRUFFLE study.
These findings demonstrate that the pattern of Doppler changes
in a fetus with IUGR may vary significantly. The weighting that
clinician should put on any one particular Doppler index will vary
with gestation, and other factors such as estimated fetal weight,
underlying medical problems, and maternal condition are impor-
tant when making the decision to deliver. In light of the TRUFFLE
study findings, which have clarified outcomes in fetuses <32
weeks' gestation, decision regarding timing of delivery still requires
individualization at later preterm gestations where the umbilical
waveform remains normal.
9. Conclusion
There is no single assessment modality that suits all antenatal
monitoring requirements at all gestational ages. There is also a
paucity of high-quality data and randomized trials to support many
monitoring modalities. The key question for the clinician caring for,
and mother of, a compromised fetus or a fetus at risk of compro-
mise is “Will delivery of this fetus improve long-term outcome?”
and this needs to be balanced against the risks to the mother. The
TRUFFLE study has at least clarified the effect on outcomes in IUGR
fetuses prior to 32 weeks, where the decision to deliver is based on
reduced CTG STV or abnormal DV [46].
At later gestations, it would seem prudent to deliver a fetus
beyond 32 weeks gestation in the presence of a persistent UA
waveform or CTG abnormality. In the growth-restricted fetus with a
normal UA waveform but raised PI > 95th centile or MCA PI < 5th
centile, delivery around 37 weeks seems reasonable.
In part, the reason for the scarcity of data to support the various
elements of antenatal monitoring is that the overall prevalence of
 T.R. Everett, D.M. Peebles / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
adverse outcomes, even in a high-risk population, is relatively low
(70/10,000), and this is ten-fold higher than the low-risk popula-
tion (7/10,000) [47,48]. Although we are now better at identifying
and monitoring high-risk women, increased intervention may be
causing adverse outcomes in fetuses who are not compromised.
Similarly, 30e50% of adverse outcomes occur in low-risk
populations.
There is a need for improved understanding of the nature of
unexplained and unexpected fetal death. To improve outcomes, this
needs to be combined with improved risk-stratification of pregnant
(and pre-pregnant women), alongside high-quality studies of
antenatal monitoring and the development of new, improved
techniques that are only introduced following adequate
assessment.
Practice points
 Tests of fetal wellbeing have to be interpreted in the
context of risk assessment.
 There is no single “best-performing” test of fetal well-
being; management decisions are always based on a
combination.
 Cardiotocography is of limited value for the antenatal
assessment of fetal wellbeing.
 If CTGs are performed antenatally, analysis should be
computerized.
 MCA dilation occurs early and is then maintained while
the fetus is hypoxic.
Research directions
 To determine the role of routine third-trimester fetal
biometry in all women to prevent stillbirth related to fetal
growth restriction.
 To determine the optimal method of initial fetal assess-
ment in women presenting with reduced fetal
movements.
 To define the role of the cerebro:placental ratio in fetal
assessment in the late third trimester.
Conflict of interest statement
None declared.
Funding sources
None.
References
[1] Richardson BS, Bocking AD. Metabolic and circulatory adaptations to chronic
hypoxia in the fetus. Comp Biochem Physiol 1998;119A:717e23.
[2] Martin Jr CB. Normal fetal physiology and behavior, and adaptive responses
with hypoxemia. Semin Perinatol 2008;32:239e42.
[3] Alfirevic Z, Devane D, Gyte GML. Continuous cardiotocography (CTG) as a form
of electronic fetal monitoring (EFM) for fetal assessment during labour.
Cochrane Database Syst Rev 2013;(5):CD006066.
[4] Dyson C, Austin T, Lees C. Could routine cardiotocography reduce long term
cognitive impairment? BMJ 2011;342:d3120.
Please cite this article in press as: Everett TR, Peebles DM, Antenatal tests of fetal wellbeing, Seminars in Fetal & Neonatal Medicine (2015),
http://dx.doi.org/10.1016/j.siny.2015.03.011
5
[5] Grivell RM, Alfirevic Z, Gyte GM, Devane D. Antenatal cardiotocography for
fetal assessment. Cochrane Database Syst Rev 2012;(12):CD007863.
[6] Royal College of Obstetricians and Gynaecologists. Small-for-gestational-age
fetus, investigation and management (Green-top Guideline No. 31). London:
RCOG; 2013.
[7] Ribbert LS, Fidler V, Visser GH. Computer-assisted analysis of normal second
trimester fetal heart rate patterns. J Perinat Med 1991;19:53e9.
[8] Turan S, Turan OM, Berg C, Moyano D, Bhide A, Bower S, et al. Computerized
fetal heart rate analysis, Doppler ultrasound and biophysical profile score in
the prediction of acidebase status of growth-restricted fetuses. Ultrasound
Obstet Gynecol 2007;30:750e6.
[9] Smith JH, Anand KJ, Cotes PM, Dawes GS, Harkness RA, Howlett TA, et al.
Antenatal fetal heart rate variation in relation to the respiratory and metabolic
status of the compromised human fetus. Br J Obstet Gynaecol 1988;95:980e9.
[10] Thompson JL, Kuller JA, Rhee EH. Antenatal surveillance of fetal growth re-
striction. Obstet Gynecol Surv 2012;67:554e65.
[11] Miller DA, Rabello YA, Paul RH. The modified biophysical profile: antepartum
testing in the 1990s. Am J Obstet Gynecol 1996;174:812e7.
[12] Lalor JG, Fawole B, Alfirevic Z, Devane D. Biophysical profile for fetal assess-
ment in high risk pregnancies. Chichester, UK: John Wiley & Sons; 2012.
[13] Alfirevic Z, Walkinshaw SA. A randomised controlled trial of simple compared
with complex antenatal fetal monitoring after 42 weeks of gestation. Br J
Obstet Gynaecol 1995;102:638e43.
[14] Lewis DF, Adair CD, Weeks JW, Barrilleaux PS, Edwards MS, Garite TJ.
A randomized clinical trial of daily nonstress testing versus biophysical profile
in the management of preterm premature rupture of membranes. Am J Obstet
Gynecol 1999;181:1495e9.
[15] Morris RK, Malin G, Robson SC, Kleijnen J, Zamora J, Khan KS. Fetal umbilical
artery Doppler to predict compromise of fetal/neonatal wellbeing in a high-
risk population: systematic review and bivariate meta-analysis. Ultrasound
Obstet Gynecol 2011;37:135e42.
[16] Morrow RJ, Ritchie JW, Bull SB. Fetal and maternal hemodynamic responses to
exercise in pregnancy assessed by Doppler ultrasonography. Am J Obstet
Gynecol 1989;160:138e40.
[17] Kingdom JC, Burrell SJ, Kaufmann P. Pathology and clinical implications of
abnormal umbilical artery Doppler waveforms. Ultrasound Obstet Gynecol
1997;9:271e86.
[18] Berkley E, Chauhan SP, Abuhamad A. Doppler assessment of the fetus with
intrauterine growth restriction. Am J Obstet Gynecol 2012;206:300e8.
[19] Beattie RB, Dornan JC, Thompson W. Intrauterine growth retardation: pre-
diction of perinatal distress by Doppler ultrasound. Lancet 1987;2:974.
[20] Goffinet F, Paris-Llado J, Nisand I, Bre art G. Umbilical artery Doppler veloc-
imetry in unselected and low risk pregnancies: a review of randomised
controlled trials. Br J Obstet Gynaecol 1997;104:425e30.
[21] Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound in
high-risk pregnancies. Chichester, UK: John Wiley & Sons, Ltd; 2013.
[22] Westergaard HB, Langhoff-Roos J, Lingman G, Mars al K, Kreiner S. A critical
appraisal of the use of umbilical artery Doppler ultrasound in high-risk
pregnancies: use of meta-analyses in evidence-based obstetrics. Ultrasound
Obstet Gynecol 2001;17:466e76.
[23] Mari G, Deter RL, Carpenter RL, Rahman F, Zimmermann R, Moise KJ, et al.
Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to
maternal red-cell alloimmunization. Collaborative Group for Doppler
Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:
9e14.
[24] Sueters M, Arabin B, Oepkes D. Doppler sonography for predicting fetal ane-
mia caused by massive fetomaternal hemorrhage. Ultrasound Obstet Gynecol
2003;22:186e9.
[25] Cosmi E, Rampon M, Saccardi C, Zanardo V, Litta P. Middle cerebral artery
peak systolic velocity in the diagnosis of fetomaternal hemorrhage. Int J
Gynaecol Obstet 2012;117:128e30.
[26] Hershkovitz R, Kingdom JC, Geary M, Rodeck CH. Fetal cerebral blood flow
redistribution in late gestation: identification of compromise in small fetuses
with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2000;15:
209e12.
[27] Fieni S, Gramellini D, Piantelli G. Lack of normalization of middle cerebral
artery flow velocity prior to fetal death before the 30th week of gestation: a
report of three cases. Ultrasound Obstet Gynecol 2004;24:474e6.
[28] Oros D, Figueras F, Cruz-Martinez R, Meler E, Munmany M, Grataco s E. Lon-
gitudinal changes in uterine, umbilical and fetal cerebral Doppler indices in
late-onset small-for-gestational age fetuses. Ultrasound Obstet Gynecol
2011;37:191e5.
[29] Severi FM, Bocchi C, Visentin A, Falco P, Cobellis L, Florio P, et al. Uterine and
fetal cerebral Doppler predict the outcome of third-trimester small-for-
gestational age fetuses with normal umbilical artery Doppler. Ultrasound
Obstet Gynecol 2002;19:225e8.
[30] Morris RK, Say R, Robson SC, Kleijnen J, Khan KS. Systematic review and meta-
analysis of middle cerebral artery Doppler to predict perinatal wellbeing. Eur J
Obstet Gynecol Reprod Biol 2012;165:141e55.
[31] Alataş C, Aksoy E, Akarsu C, Yakin K, Bahçeci M. Prediction of perinatal
outcome by middle cerebral artery Doppler velocimetry. Archs Gynecol Obstet
1996;258:141e6.
[32] Prior T, Mullins E, Bennett P, Kumar S. Prediction of intrapartum fetal
compromise using the cerebroumbilical ratio: a prospective observational
study. Am J Obstet Gynecol 2013;208:124.e1e6.
6 T.R. Everett, D.M. Peebles / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
[33] Khalil AA, Morales Rosello  J, Morlando M, Hannan H, Bhide A,
Papageorghiou A, et al. Is fetal cerebroplacental ratio an independent pre-
dictor of intrapartum fetal compromise and neonatal unit admission? Am J
Obstet Gynecol 2014 Oct 18. pii: S0002e9378(14)01079-5 [Epub ahead of
print].
[34] Prior T, Paramasivam G, Bennett P, Kumar S. Are babies that fail to reach their
genetic growth potential at increased risk of intra-partum fetal compromise?
Ultrasound Obstet Gynecol 2014 Dec 9 [Epub ahead of print].
[35] Morales-Rosello  J, Khalil A, Morlando M, Bhide A, Papageorghiou A,
Thilaganathan B. Poor neonatal acidebase status in term fetuses with low
cerebroplacental ratio. Ultrasound Obstet Gynecol 2015;45:156e61.
[36] Flood K, Unterscheider J, Daly S, Geary MP, Kennelly MM, McAuliffe FM, et al.
The role of brain sparing in the prediction of adverse outcomes in intrauterine
growth restriction: results of the multicenter PORTO Study. Am J Obstet
Gynecol 2014;211:288.e1e5.
[37] Bhide A, Acharya G, Bilardo CM, Brezinka C, Afici DC, Hernadez-Andrade E,
et al. ISUOG practice guidelines: use of Doppler ultrasonography in obstetrics.
Ultrasound Obstet Gynecol 2013;41:233e9.
[38] Baschat AA, Galan HL, Bhide A, Berg C, Kush ML, Oepkes D, et al. Doppler and
biophysical assessment in growth restricted fetuses: distribution of test re-
sults. Ultrasound Obstet Gynecol 2006;27:41e7.
[39] Baschat AA. Ductus venosus Doppler for fetal surveillance in high-risk preg-
nancies. Clin Obstet Gynecol 2010;53:858e68.
[40] Baschat AA, Gembruch U, Weiner CP, Harman CR. Qualitative venous Doppler
waveform analysis improves prediction of critical perinatal outcomes in
premature growth-restricted fetuses. Ultrasound Obstet Gynecol 2003;22:
240e5.
Please cite this article in press as: Everett TR, Peebles DM, Antenatal tests of fetal wellbeing, Seminars in Fetal & Neonatal Medicine (2015),
http://dx.doi.org/10.1016/j.siny.2015.03.011
[41] Bilardo CM, Wolf H, Stigter RH, Vile Y, Baez E, Visser GHA, et al. Relationship
between monitoring parameters and perinatal outcome in severe, early in-
trauterine growth restriction. Ultrasound Obstet Gynecol 2004;23:119e25.
[42] Thornton JG, Hornbuckle J, Vail A, Spiegelhalter DJ, Levene M. GRIT study
group. Infant wellbeing at 2 years of age in the Growth Restriction Inter-
vention Trial (GRIT): multicentred randomised controlled trial. Lancet
2004;364(9433):513e20.
[43] Walker DM, Marlow N, Upstone L, Gross H. The Growth Restriction Inter-
vention Trial: long-term outcomes in a randomized trial of timing of delivery
in fetal growth restriction. Am J Obstet Gynecol 2011;204. 34.e1e9.
[44] Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A, Pardi G, et al. Temporal
sequence of abnormal Doppler changes in the peripheral and central circu-
latory systems of the severely growth-restricted fetus. Ultrasound Obstet
Gynecol 2002;19:140e6.
[45] Unterscheider J, Daly S, Geary MP, Kennelly MM, McAuliffe FM, O'Donoghue K,
et al. Predictable progressive Doppler deterioration in IUGR: does it really
exist? Am J Obstet Gynecol 2013;209. 539.e1e7.
[46] Lees CC, Marlow N, van Wassenaer-Leemhuis A, Arabin B, Bilardo CM,
Brezinka C, et al. 2 year neurodevelopmental and intermediate perinatal
outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a
randomised trial. Lancet 2015 Mar 4. pii: S0140e6736(14)62049-3 [Epub
ahead of print].
[47] OʼNeill E, Thorp J. Antepartum evaluation of the fetus and fetal well being. Clin
Obstet Gynecol 2012;55:722e30.
[48] Haws RA, Yakoob MY, Soomro T, Menezes EV, Darmstadt GL, Bhutta ZA.
Reducing stillbirths: screening and monitoring during pregnancy and labour.
BMC Pregnancy Childbirth 2009;9(Suppl. 1):S5.