Original Research ajog.

org

OBSTETRICS
Early and late preeclampsia are characterized by high
cardiac output, but in the presence of fetal growth
restriction, cardiac output is low: insights from a
prospective study
Jasmine Tay, BMBS, MRCOG; Lin Foo, BM BSc; Giulia Masini, MD; Phillip R. Bennett, MD, PhD, BSc, FRCOG;
Carmel M. McEniery, PhD; Ian B. Wilkinson, MA DM FRCP; Christoph C. Lees, MD, MRCOG

BACKGROUND: Preeclampsia and fetal growth restriction are
considered to be placentally mediated disorders. The clinical manifestations
are widely held to relate to gestation age at onset with early- and late-onset
preeclampsia considered to be phenotypically distinct. Recent studies have
reported conflicting findings in relation to cardiovascular function, and in
particular cardiac output, in preeclampsia and fetal growth restriction.
OBJECTIVE: We conducted this study to examine the possible relation
between cardiac output and peripheral vascular resistance in preeclampsia
and fetal growth restriction.
STUDY DESIGN: We investigated maternal cardiovascular function in
relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia
only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth
restriction) and compared these with 107 healthy person observations.
Cardiac output was the primary outcome measure and was assessed using
an inert gas-rebreathing method (Innocor), from which peripheral vascular
resistance was derived; arterial function was assessed by Vicorder, a cuff-
based oscillometric device. Cardiovascular parameters were normalized for
gestational age in relation to healthy pregnancies using Z scores, thus
allowing for comparison across the gestational range of 24e40 weeks.
RESULTS: Compared with healthy control pregnancies, women with
preeclampsia had higher cardiac output Z scores (1.87
1.35; P ¼
.0001) and lower peripheral vascular resistance Z scores (e0.76
0.89;
P ¼ .025); those with fetal growth restriction had higher peripheral
vascular resistance Z scores (0.57
1.18; P ¼ .04) and those with both
preeclampsia and fetal growth restriction had lower cardiac output Z
scores (e0.80
1.3 P ¼ .007) and higher peripheral vascular resistance
Z scores (2.16
1.96; P ¼ .0001). These changes were not related to
gestational age of onset. All those affected by preeclampsia and/or fetal
growth restriction had abnormally raised augmentation index and pulse
wave velocity. Furthermore, in preeclampsia, low cardiac output was
associated with low birthweight and high cardiac output with high birth-
weight (r ¼ 0.42, P ¼ .03).
CONCLUSION: Preeclampsia is associated with high cardiac output,
but if preeclampsia presents with fetal growth restriction, the opposite is
true; both conditions are nevertheless defined by hypertension. Fetal
growth restriction without preeclampsia is associated with high peripheral
vascular resistance. Although early and late gestation preeclampsias are
considered to be different diseases, we show that the hemodynamic
characteristics of preeclampsia were unrelated to gestational age at onset
but were strongly associated with the presence or absence of fetal growth
restriction. Fetal growth restriction more commonly coexists with pre-
eclampsia at early gestation, thus explaining the conflicting results of
previous studies. Furthermore, antihypertensive agents act by reducing
cardiac output or peripheral vascular resistance and are administered
without reference to cardiovascular function in preeclampsia. The un-
derlying pathology (preeclampsia, fetal growth restriction, preeclampsia
and fetal growth restriction) defines cardiovascular phenotype, providing a
rational basis for choice of therapy in which high or low cardiac output or
peripheral vascular resistance is the predominant feature.
Key words: arterial function, cardiac output, hypertension, pregnancy,
vascular resistance

P reeclampsia (PE) is not simply a

pregnancy-specific syndrome: its
implications on later life cardiovascular1
and cognitive function2 and health care
cost3 are only now being understood. Fetal
growth restriction (FGR) has a close but
poorly understood relationship with PE.
Cite this article as: Tay J, Foo L; Masini G, et al. Cardiac
output in preeclampsia is associated with the presence
of fetal growth restriction, not gestation at onset: a
prospective cohort study. Am J Obstet Gynecol
2017;xxx:xx-xx.
0002-9378/$36.00
ª 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2018.02.007
Although PE and FGR frequently
present in isolation, they may occur
together, particularly at early gestation.4
The underlying pathophysiology of
PE has never been fully understood, but
the cause has often been attributed to
the placenta because PE resolves
completely after delivery. Inadequate
trophoblast invasion leading to utero-
placental malperfusion is thought to
underlie both PE and FGR.5,6 However,
this placental theory does not explain
why women who had PE in their preg-
nancies have a higher cardiovascular
risk in later life7-9 or why women
with prepregnancy cardiovascular risk
factors have a higher risk of PE and FGR
in pregnancy.10
Emerging data suggest that maternal
cardiovascular function is impaired after
delivery in women with PE,11,12 and
high blood pressure prior to pregnancy
increases the risk of PE developing.10
Nevertheless, PE and FGR are commonly
referred to as placenta-mediated disor-
ders, suggested to arise through defective
placentation.
Studies of cardiovascular function in
pregnancy have shown inconsistent
and, in some cases, contradictory re-
sults. The classic studies of Easterling
et al13 suggested that PE was associated

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Materials and Methods

AJOG at a Glance
Study protocol
Research question: why was this study conducted? In this prospective cross-sectional study,
To resolve the unanswered questions as to the precise hemodynamic changes in women between weeks 24 and 40 of
pregnancies complicated by preeclampsia, fetal growth restriction, and the pregnancy were recruited from the
combination of the 2 and whether gestation at onset determines these changes. antenatal clinic, labor ward, day assess-
ment unit, and antenatal ward of a
Key Findings tertiary-level London teaching hospital
In preeclampsia, cardiac output is high and peripheral resistance low. In fetal between January 2015 and May 2017.
growth restriction with preeclampsia, the opposite is true, and in growth re- The study protocol was approved by
striction, there is increased peripheral resistance. Arterial function is abnormal in National Health Service National
all cases. Research Ethics Committee, London
Riverside, and all participants gave
What does this add to what is known? written informed consent. Gestation of
Preeclampsia and fetal growth restriction are associated with distinctly different pregnancy was determined by measure-
and opposing cardiovascular phenotypes that are not related to gestation of onset. ment of crown-rump length between 11
These findings may be important in monitoring maternal and fetal condition and and 13 weeks in early pregnancy.
guiding therapy. Women were recruited at presentation
or diagnosis where it was feasible to
conduct a detailed cardiovascular
with a high cardiac output (CO) state, gestational age cutoff. This distinction examination and were not included if
although this relationship was thought arose not because of a pathophysiological they were already in labor, undergoing
to be explained, at least in part, by the difference between the conditions but induction of labor, or imminent delivery
increased body surface area.14 Other because of the inability of screening by was planned (Figure 1). We describe the
studies have suggested that PE should uterine artery Doppler to effectively diagnosis as those with PE alone (PE
be subdivided into those in which low identify cases of late-onset disease.21-23 It is only), FGR alone (FGR only), and PE
or high CO is predominant.15 suggested that early and late variants have together with FGR (PE and FGR).
FGR with and without PE have a different underlying vascular characteris- Women’s assessments are reported at the
different cardiovascular profile16,17 tics, although in most studies, late PE is time of initial diagnosis of 1 of these
although the relationship of these rarely or never associated with FGR.20 conditions, and the diagnosis assigned at
changes to a healthy pregnancy or PE Adding further complexity, recent studies the time of study inclusion.
without FGR has not been studied. A have suggested that PE at term is associ- One hundred seven healthy person
recent systematic review concluded that ated with babies with larger birthweight.14 observations acted as control cases with
studies of cardiovascular function in We sought to investigate the relation- no control subject assessed twice within
gestational hypertension and PE show ship between cardiovascular function and the same epoch. PE was defined as blood
conflicting results. The authors concluded clinical phenotype of PE and FGR alone pressure at diagnosis of >140/90 mm Hg
that “increased peripheral vascular resis- and in combination across a gestation and urine protein creatinine ratio of >30.
tance correlates with disease severity,” but range, with cardiac output being the FGR was defined as fetal abdominal
of note, the coexistence of FGR was not primary outcome measure. Cardiovas- circumference or estimated fetal weight
considered in a majority of the studies.18 cular function changes with gestational <10th centile24 and umbilical Doppler
Previous studies on cardiovascular age, therefore, to allow comparison, we PI >95th centile on ultrasound scan.25
function in PE have incompletely char- transformed all data in relation to that Those women with known underlying
acterized FGR,19 recruited only within a obtained from women with healthy cardiovascular conditions, multiple
particular gestational range16 and/or not pregnancies using the statistical tech- pregnancies, and fetal anomalies were
compared findings with a healthy refer- nique of Z scoring. This removed the excluded from the study.
ence pregnant population.20 Existing need for a gestation-matched cohort Participants underwent peripheral
studies provide interesting insights to design and allowed all data points to be blood pressure measurement, compre-
cardiovascular dysfunction in patholog- considered.19 In doing so, we performed hensive cardiovascular assessments, and
ical pregnancies but leave important comprehensive hemodynamic assess- fetal ultrasound scans as detailed in the
questions unanswered in relationship ments from 24 weeks’ gestation onward following text.
with gestational effects and pregnancies in women with healthy pregnancies, with
in which PE and FGR are combined. PE in combination with FGR (PE and Cardiovascular assessments
Over the last 2 decades, it has become FGR), PE without FGR (PE only), and Participants were requested to abstain
customary to subdivide PE into early and FGR without PE (FGR only), managed from caffeinated drinks for 4 hours
late variants with an arbitrary 34 week and monitored in a single maternity unit. before the visit. In brief, cardiovascular

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ajog.org OBSTETRICS Original Research

FIGURE 1
Recruitment flow chart

Approached for recruitment

n= 163

Paent declined

n= 8

Controls recruited Pathology included

n= 110 n= 45

Excluded

n=1 (Umbillical PI
>95th cenle)

n=1 (Significant
antepartum
haemorrhage leading
to preterm delivery)
PE FGR PE and FGR
n=1 (no birthweight
data) n= 14 n= 16 n= 15

Controls included

n= 107

FGR, fetal growth restriction; PE, preeclampsia; PI, pulsatility index.

Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.

measurements were performed with the measured using Innocor, a noninvasive Europe B.V., Hoofddorp, Netherlands),
patient standing upright for the assess- inert gas-rebreathing technique as pre- which has been validated in pregnancy.28
ment of cardiac output and in the left viously described.26,27 Blood pressure was measured on the right
lateral lying position for assessment of Brachial blood pressure was measured arm in the seated position following
arterial function. Cardiac output was using Omron M-7 (OMRON Healthcare recommendations from the European

TABLE 1
Demographic characteristics at recruitment
Kruskal-Wallis
Characteristics Controls FGR PE PE and FGR P value
Cases, n 107 16 14 15 —
Gestational age at recruitment, median (range) 32 (24e40) 32 (24e39) 36 (25e39) 30 (24e36) .500
Parity, median (range) 1 (0e3) 0 (0e2) 0 (0e2) 0.5 (0e3) —
Age, median (IQR) 34 (31.5e36.5) 35 (31e39) 32 (27.5e36.5) 33 (31e35) .110
a
Booking BMI, mean (SD) 24 (3.2) 25.7 (5.6) 29.1 (4.5) 25.8 (5.4) .007
BMI, body mass index; FGR, fetal growth restriction; IQR, interquartile ratio; PE, preeclampsia.
a
P ¼ .001 between controls and PE.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.

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TABLE 2
Cardiovascular parameters (by gestation epochs for control cases) and overall values for pathological outcome cases
[mean (SD)]
Variables Gestation Controls FGR PE PE and FGR
CO standing, l/min 24e27þ6 6.2 (0.92) 5.56 (1.06) 7.23 (1.37) 5.22 (1.22)
þ6
28e31 6.0 (0.97)
þ6
32e35 5.74 (1.13)
36e40 5.34 (0.84)
PVR, dyn per s/cm 24e27þ6 1088.7 (217.9) 1311.6 (291.6) 1091.6 (232.2) 1648.5 (430.1)
þ6
28e31 1148.34 (270)
þ6
32e35 1187.97 (200.2)
36e40 1303.18
þ6
Aortic AIx, U 24e27 14.22 (7.7) 22.2 (12.3) 29.7 (14.9) 25.8 (9.4)
28e31þ6 11.3 (7.7)
32e35þ6 11.2 (8.9)
36e40 14.1 (10.7)
1 þ6
PWV, m/s 24e27 6.8 (0.9) 7.84 (1.32) 7.8 (1.38) 8.82 (1.37)
þ6
28e31 7.0 (1.1)
32e35þ6 7.0 (0.9)
36e40 7.2 (0.9)
þ6
Pulse, beats/min 24e27 80.4 (10.3) 78.7 (12.5) 83.8 (10.2) 76.1 (9.9)
þ6
28e31 83.5 (14.3)
þ6
32e35 87 (13.2)
36e40 86 (11)
þ6
MAP 24e27 81.1 (7.1) 87.9 (9.6) 95.2 (7.2) 102.4 (10.8)
þ6
28e31 77.8 (8.2)
þ6
32e35 79.1 (4.8)
36e40 81.6 (7.8)
AIx, augmentation index; CO, cardiac output; FGR, fetal growth restriction; MAP, mean arterial pressure; PE, preeclampsia; PVR, peripheral vascular resistance; PWV, pulse wave velocity.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.

Society of Hypertension.29 Mean arterial
pressure was calculated by (diastolic
pressure þ [systolic pressure e diastolic
pressure)/3]). Peripheral vascular resis-
tance (PVR) was derived with the
following formula: PVR ¼ mean arterial
pressure  80/cardiac output.
Arterial analysis was performed using
the Vicorder (Skidmore Medical, Bris-
tol, United Kingdom), an oscillometric
device validated for the measurements
of augmentation index (AIx) and pulse
wave velocity (PWV).30 With the pa-
tient lying in the left lateral position, a
brachial cuff was applied to the right
upper arm, a leg cuff applied to the right
upper thigh, and a neck sensor posi-
tioned over the carotid artery. A stan-
dard measuring tape was used to
measure the linear distance between the
suprasternal notch and a defined point
on the femoral cuff. The AIx, PWV, and
maternal heart rate (beats per minute)
were recorded.
Ultrasound
Obstetric ultrasound assessment was
performed on Samsung WS80 equip-
ment (Samsung Medison, Seoul,
Republic of Korea). Fetal growth pa-
rameters (head circumference, biparietal
diameter, abdominal circumference, and
femur length) and Doppler studies
(umbilical, middle cerebral artery, duc-
tus venosus, and uterine artery) were
recorded in all pathological pregnancy
cases.
Statistical analysis
Statistical analyses were performed using
SPSS (version 24-0-0, 2016; SPSS Inc,
Chicago, IL). The Kruskal-Wallis test was
used to compare the demographic char-
acteristics between the 4 groups. The
normality of distribution of the data was
examined with the Shapiro-Wilk test, and
histograms and data are expressed as
means
SD or medians (interquartile

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ajog.org OBSTETRICS Original Research

TABLE 3
Z scores of cardiovascular parameters by outcome group (controls are reference)
Variables FGR PE PE and FGR
CO standing e0.35 (0.99) 1.87 (1.35)a e0.80 (1.3)a
PVR standing 0.57 (1.18)a e0.76 (0.89)a 2.16 (1.95)a
AIx 1.18 (1.44)a 1.52 (1.39)a 1.45 (1.09)a
PWV 0.87 (1.34)a 0.71 (1.47)a 2.01 (1.55)a
AIx, augmentation index; CO, cardiac output; FGR, fetal growth restriction; PE, preeclampsia; PVR, peripheral vascular resistance; PWV, pulse wave velocity.
a
P < .05 compared with corresponding control value.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.

range) for normally and nonnormally
distributed data, respectively.
We analyzed the data using body mass
index, age, and ethnicity as covariates.
Because cardiovascular function changes
with gestational age and to compare
hemodynamic characteristics across
groups with different gestational ages, we
transformed all data in relation to that
obtained from women with healthy
pregnancies using the statistical technique
of Z scoring. This removed the need for a
FIGURE 2
Z score of PVR (standing) in pathological outcome groups (median, IQR)
gestation-matched cohort design and
allowed all data points to be considered.16
Briefly, measurements were trans-
formed to the corresponding Z scores
with reference to means and SD values
derived from controls in 4-weekly
gestational epochs (24e27þ6; 28e31þ6;
32e35þ6; and 36e39þ6 weeks) for CO,
PVR, Aix, and PWV. The Z scores of each
cardiovascular parameter were then
compared using an unpaired Student
t test. In our cohort, heart rate did not
change with gestation and comparisons
were made with untransformed data.
Results
Forty-five pathological pregnancies (14 PE
only, 16 FGR only, and 15 PE and FGR)
were recruited, of whom 3 had a prior
history of PE and/or FGR. All women
remained within the category to which
they were first assigned at recruitment. A
further 64 women with healthy pregnan-
cies and normal pregnancy outcomes were
studied across the gestation, yielding 107
healthy pregnancy observations.
A Kruskal- Wallis test showed no sta-
tistically significant differences between
age and ethnicity within the 4 groups.
The group with PE had a higher booking
body mass index when compared with
the control group (P ¼ .001) (Table 1).
Cardiovascular parameters in patho-
logical and control groups are presented
in Table 2. The cardiovascular parameters
in pathological pregnancies are presented
in Table 3; Z scores were calculated in
relation to control cases from healthy
pregnancies, which were subdivided into
4 weekly gestational epochs.

FGR only
In women with FGR only, PVR Z score
was significantly higher (0.57
1.18, P ¼
.04) (Figure 2), and the CO Z score was
no different from healthy controls (e0.35

0.99, P ¼ .19) (Figure 3). The Z scores
of AIx (1.18
1.44, P ¼.0001) (Figure 4)
and PWV (0.87
1.34, P ¼ .002)
(Figure 5) were higher than controls.

FGR, fetal growth restriction; IQR, interquartile ratio; PE, preeclampsia; PVR, peripheral vascular resistance.
PE only
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018. Women with PE only had a higher CO Z
score than controls 1.87
1.35, P ¼

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Original Research
FIGURE 3
Z score of CO (standing) in pathological outcome groups (median, IQR)
CO, cardiac output; FGR, fetal growth restriction; IQR, interquartile ratio; PE, preeclampsia.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.
.0001) (Figure 3), a lower PVR Z score
(e0.76
0.89, P ¼ .025) (Figure 2), a
higher AIx Z score (1.52
1.39, P ¼
.0001) (Figure 4), and higher PWV (0.71

1.47, P ¼ .05) (Figure 5).
Of the 13 women with PE only, 7
women were examined before starting
antihypertensive medication, 3 women
were on labetalol, and 1 on nifedipine.
The Z scores for CO and PVR of those
examined on treatment vs those without
were not different (P ¼ 0.55 and P ¼.57,
respectively).
PE and FGR
In PE and FGR cases, a lower CO Z score
(e0.80
1.3, P ¼ .007) (Figure 3) and a
higher PVR Z score (2.16
1.95, P ¼
.0001) (Figure 2) were observed
compared with controls. There was a
higher AIx Z score (1.45
1.09, P ¼
.0001) (Figure 4) and a higher PWV Z
score (2.01
1.55, P ¼.0001) (Figure 5).
Of the 14 women with PE and FGR, 3
were examined before starting antihy-
pertensive medication, and 4 were taking
1.e6 American Journal of Obstetrics & Gynecology MONTH 2018
OBSTETRICS
labetalol, 2 nifedipine, and 3 both labe-
talol and nifedipine. Comparing the Z
scores for CO and PVR of those exam-
ined on treatment vs those without,
there were no differences (P ¼ .52 and
P ¼ .99, respectively).
Heart rate
There was no difference in observed
heart rate between the 4 groups.
(P ¼ .26) (Figure 6).
Gestation vs CO/PVR
When compared across gestation (deci-
mal weeks by estimated due date derived
from dating scan), there was no rela-
tionship between gestation and either
CO Z score (Pearson correlation, 0.16,
P ¼ .35) or PVR Z score (Pearson cor-
relation, e0.21, P ¼.2) for PE only, FGR
only, and PE and FGR.
There was no difference between CO
Z score (P ¼ .41) or PVR Z score (P ¼
.18) in PE only prior to 34 weeks and
those after 34 weeks. In combined PE
and FGR cases, there was again no
ajog.org
difference between CO Z score (P ¼ .34)
or PVR Z score (P ¼.76) in cases prior to
34 weeks and those after.
CO vs Z score birthweight
Within the group of women with PE (PE
only and PE and FGR), CO was posi-
tively associated with Z score birthweight
(r ¼ 0.42, P ¼ .03). Within the group of
women with FGR only, CO was not
associated with Z score birthweight (r ¼
0.27, P ¼ .31).
Post hoc power calculation
Because this was novel work, a formal
sample size calculation prior to under-
taking the study was not possible, and
the enrollment period was guided by our
previous prepregnancy studies in healthy
women.27,31,32 However, a formal post
hoc power calculation, assuming 4 un-
equal groups and an SD for the CO Z
score equivalent to the highest SD ob-
tained in the 3 pathological pregnancy
groups, gave >98% power to detect a
significant overall difference in CO Z
score, at an alpha level of 0.05.
Comment
We report that women with PE only,
FGR only, and PE and FGR have
distinctly different and, in some cases,
opposing cardiovascular characteristics.
The predominant abnormalities in PE
only were a higher CO and lower PVR,
while FGR only was characterized by
higher PVR than healthy pregnancies.
When both PE and FGR occur together,
the effect was a cardiovascular pheno-
type characterized by a markedly higher
PVR and lower CO than FGR only.
Previous studies of PE and FGR have
reported inconsistent findings; however,
none have studied hemodynamic find-
ings across the whole gestation range in
relation to healthy pregnancies recruited
concurrently nor have considered FGR,
PE, and PEFGR as separate entities.
Recently a meta-analysis by Castle-
man et al18 found that in gestational
hypertensive diseases, “severity of dis-
ease corresponded with increasing
vascular resistance.” We suggest that this
is an oversimplification in that according
to our data, it holds for PE with FGR, the
converse being true for PE not affected
ajog.org
FIGURE 4
Z score of augmentation index in pathological outcome groups (median, IQR)
FGR, fetal growth restriction; IQR, interquartile ratio; PE, preeclampsia.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.
by FGR.18 Irrespective of differences in
CO and PVR, all 3 pregnancy compli-
cations were associated with abnormal
arterial function assessed by increased
augmentation index and increased pulse
wave velocity.
The implications for understanding of
the disease process is important, partic-
ularly in respect of the deeply ingrained
but empirical and arbitrary distinction
between early and late PE with a cutoff at
34 weeks.22,33 It is true that the cardio-
vascular features of early and late PE
were different, but this was purely by
virtue of the association with FGR rather
than because of the gestational age at
onset of the disease.
PE only had the same cardiovascular
findings (high CO and low PVR) at early
and late gestational ages, but if PE was
associated with FGR, CO was low and
PVR high, irrespective of gestational age.
Importantly, in our study, pathological
cases were similarly represented in nu-
merical terms before and after 34 weeks,
24 and 21 cases, respectively.
OBSTETRICS
The contradictory findings of previ-
ous studies, namely that gestational age
is the determinant of hemodynamic
profile in PE, may be explained because
PE and FGR commonly coexist at early
gestational ages34 and FGR is uncom-
monly encountered in late PE.14 PE is
therefore more precisely defined by the
presence or absence of FGR rather than
by virtue of its gestational age at onset.
We trace the origins of the categorization
of early and late PE to a study on the
sensitivity of second-trimester uterine
artery Doppler for these complications,
which was high for early but low for late
disease. Interestingly, early PE was
frequently found with FGR in that study.
In women with PE, with and without
FGR, we found a significant positive
association between CO Z score and
birthweight normalized for gestation,
which was no different before or after 34
weeks. We did not specifically select
women with PE, with and without FGR,
but instead recruited all comers and
categorized FGR based on ultrasound
MONTH 2018 American Journal of Obstetrics & Gynecology
Original Research
and Doppler findings. Hence, there was
no selection bias within women with PE
because it might be argued that a larger
fetus and placenta will drive a larger CO.
We previously reported that the in-
cremental increase in maternal CO from
prior to pregnancy to the midsecond
trimester was positively associated with
larger birthweight in normally grown
babies35 irrespective of the size of the
fetus in the midtrimester. This suggests
that fetal size on its own did not deter-
mine CO. A recent study in women with
PE found that those with the lowest CO
had the smallest babies.15 There is strong,
albeit circumstantial, evidence that CO
may be at least in part responsible for
birthweight, likely mediated through an
effect on uteroplacental perfusion.
Although this is tempting to speculate, we
cannot infer causality from our results.
Of direct clinical relevance is that the
current management of hypertension in
pregnancy is exclusively based on a one-
size-fits-all philosophy whereby blood
pressure alone is the target of therapy,
irrespective of the underlying aeti-
ology.36,37 This approach does not
distinguish between PE with FGR (low
CO and high PVR) from PE without
FGR (high CO). There is, however, a
clear rationale in targeting therapy ac-
cording to the underlying cardiovascular
phenotype.
Drugs with beta-blocking activity are
negatively chronotropic and reducing
CO may be harmful in women with FGR
in which the uteroplacental circulation is
already impaired; previous studies have
reported an association with small-for-
gestational-age babies.38-40 We report
that PE only was typically associated
with high CO: for these women, a beta
blocker might be preferable, whereas a
drug leading to vasodilation primarily,
such as a calcium channel antagonist,
may be less effective.
Conversely, calcium antagonists are
likely to be more effective in the high-
PVR state that characterizes PE with
FGR. Although a model using hemody-
namic parameters to determine response
to labetalol in gestational hypertension
has been reported,41 the effectiveness of
antihypertensive agents with different
modes of action has not. Indeed, if
1.e7
Original Research
FIGURE 5
Z score of pulse wave velocity in pathological outcome groups (median, IQR)
FGR, fetal growth restriction; IQR, interquartile ratio; PE, preeclampsia.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.
impaired uteroplacental function is the
byproduct of a low COehigh PVR state
such as that found in PE with FGR, then
this should be amenable to targeted
manipulation. Recent approaches have
included expanding the intravascular
compartment,42 with and without nitro-
vasodilators43 and calcium antagonists44
with reported improvement in maternal
cardiovascular and/or fetal parameters.
Arterial function was abnormal in PE
only, FGR only, and the combination of
both PE and FGR as assessed by AIx and
PWV, irrespective of whether CO and
PVR were increased or decreased. Aortic
AIx is an index of wave reflection and
may be considered as a measure of arte-
rial function.45-48 Raised AIx is an
important predictor of future cardiovas-
cular risk49 and in hypertensive patients
an independent predictor of future
myocardial infarction.50 Although AIx is
influenced by endothelial function, PWV
describes aortic stiffness and is deter-
mined largely by the elastic component of
large vessels. It is also known to be a
1.e8 American Journal of Obstetrics & Gynecology MONTH 2018
OBSTETRICS
reliable marker of cardiovascular risk in
patients with hypertension.51
The strength of this study is that
detailed cardiovascular assessments were
undertaken in women who were pheno-
typed according to accepted definitions for
both PE and FGR. Importantly, our
definition of FGR did not rely simply on
fetal smallness52 but required abnormal
fetal umbilical artery Doppler. Our sample
size allowed a high power to detect small
differences in CO between the groups.
A weakness is that because our pro-
tocol required time-consuming exami-
nations, not all women wanted to or
could take part, in particular in which
delivery or further therapy was being
planned. This limited the number of
women eligible for recruitment, but
there was no attempt at selection other
than through women consenting or
otherwise for logistical and therapeutic
reasons. Furthermore, although we
intended to recruit women prior to
starting antihypertensive treatment,
these drugs were often started prior to
ajog.org
hospital admission. Although we found
no difference in CO and PVR within the
PE only and PE and FGR groups, for
those on antihypertensive treatment, the
modest numbers within these groups
preclude discrimination between small
effect sizes in antihypertensive agents
and the duration of therapy.
Although not being validated specif-
ically in pregnancy, Innocor has been
validated extensively in healthy pop-
ulations and those with diseases,
including chronic heart failure and dur-
ing hemodynamic perturbation caused
by exercise as a method of assessing car-
diac output.53-56 In addition, our group
has previously shown that this method
has good reproducibility in pregnant
women and is sensitive enough to detect
longitudinal changes in CO both in very
early pregnancy and throughout the
gestational period.27,35,57
All our participants were examined in
a similar position, which limits any po-
tential bias. Moreover because the gas-
rebreathing method is not operator
dependent, there is no interobserver bias
compared with echocardiography, which
is the other widely used method. The
Vicorder has been validated for use
against SphygmoCor, which is the most
widely used technique to assess pulse
wave velocity. There is no agreed gold
standard noninvasive technique to assess
pulse wave velocity in pregnancy.58
In summary, we found no evidence
to support the categorization of PE of
early and late as different disease pro-
cesses, although early-onset PE was much
more likely to be associated with FGR.
The significance of this is that PE, which
is not associated with FGR, has the same
cardiovascular phenotype, namely high
CO, whether it is diagnosed at 24 or 36
weeks. The presence of FGR was associ-
ated with high PVR, whether or not in
combination with PE. Whether the
abnormal hemodynamic profiles that we
have observed in the distinct subtypes of
PE, FGR, and PE combined with FGR are
the cause of the clinical manifestation of
hypertension and FGR or the effect of an
inherent underlying maternal cardiovas-
cular dysfunction is unclear.
This study raises an intriguing ques-
tion as to whether the cardiovascular
ajog.org
FIGURE 6
Heart rate in controls and pathological outcome groups (median, IQR)
There was no difference in pathological outcome groups compared with controls.
FGR, fetal growth restriction; IQR, interquartile ratio; PE, preeclampsia.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.
dysfunction seen in pathological preg-
nancies is a result of maladaptation to
the increased cardiovascular demands of
pregnancy in a woman with normal
cardiovascular function or is predis-
posed by an inherently abnormal pre-
pregnancy cardiovascular status and its
expression modulated through placental
release of vasoactive substances. n randomized umbilical and fetal flow in Europe
Acknowledgments
We thank the participants for taking part at what
for many was a critical and difficult point in their
pregnancies. Author contributions include the
following: J.T. was involved in data collection,
statistical analysis, and drafting the manuscript.
L.F., G.M., and C.M.M. contributed to analysis
and interpretation of the manuscript. P.B.,
C.M.M., I.B.W., and C.C.L. were involved in
project supervision and manuscript editing.
C.C.L. conceived the idea for this study and is
the principal investigator.
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Author and article information
From the Centre for Fetal Care, Queen Charlotte’s and
Chelsea Hospital, Imperial College Healthcare National
Health Service Trust, London (Dr Tay, Foo, Masini, and
Lees); Department of Experimental Medicine and
Immunotherapeutics, ACCI, Level 3, Addenbrooke’s,
Cambridge (Drs McEniery and Wilkinson); Institute for
Reproductive and Developmental Biology, Department of
Surgery and Cancer, Imperial College London, London
(Drs Tay, Foo, Bennett, and Lees), United Kingdom; and
Department of Development and Regeneration, KU
Leuven, Leuven, Belgium (Dr Lees).
Received Dec. 30, 2017; revised Jan. 30, 2018;
accepted Feb. 8, 2018.
J.T. is supported by Imperial College National Health
Service Trust with support from the Imperial Healthcare
Charities. C.C.L. and P.B. are supported by the UK
National Institute for Health Research Biomedical
Research Centre based at Imperial College Healthcare
National Health Service Trust and Imperial College
London. C.M.M. is supported in part by the National
Institute for Health Research Cambridge Biomedical
Research Centre. L.F. is supported by Action Medical
Research, Tommy’s and the Genesis Research Trust.
The authors report no conflict of interest.
Corresponding author: Christoph C. Lees, MD,
MRCOG. christoph.lees@nhs.net
ajog.org OBSTETRICS Original Research

SUPPLEMENTAL FIGURE 1
Scatter diagram of CO vs gestation (recruitment) in pathology cases

CO, cardiac output; FGR, fetal growth restriction; PE, preeclampsia.

Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.

MONTH 2018 American Journal of Obstetrics & Gynecology 1.e11

Original Research OBSTETRICS ajog.org

SUPPLEMENTAL FIGURE 2
Scatter diagram of PVR vs gestation (recruitment) in pathology cases

FGR, fetal growth restriction; PE, preeclampsia; PVR, peripheral vascular resistance.
Tay et al. Cardiac output in preeclampsia is associated with fetal growth restriction. Am J Obstet Gynecol 2018.

1.e12 American Journal of Obstetrics & Gynecology MONTH 2018