Original Research ajog.

org

OBSTETRICS
Maternal hemodynamics: a method to classify
hypertensive disorders of pregnancy
Enrico Ferrazzi, MD; Tamara Stampalija, MD, PhD; Lorenzo Monasta, MD; Daniela Di Martino, MD, PhD;
Sharona Vonck, MD, PhD; Wilfried Gyselaers, MD, PhD

BACKGROUND: The classification of hypertensive disorders of
pregnancy is based on the time at the onset of hypertension, proteinuria,
and other associated complications. Maternal hemodynamic interrogation
in hypertensive disorders of pregnancy considers not only the peripheral
blood pressure but also the entire cardiovascular system, and it might help
to classify the different clinical phenotypes of this syndrome.
OBJECTIVE: This study aimed to examine cardiovascular parameters in
a cohort of patients affected by hypertensive disorders of pregnancy ac-
cording to the clinical phenotypes that prioritize fetoplacental character-
istics and not the time at onset of hypertensive disorders of pregnancy.
STUDY DESIGN: At the fetal-maternal medicine unit of Ziekenhuis
Oost-Limburg (Genk, Belgium), maternal cardiovascular parameters were
obtained through impedance cardiography using a noninvasive continuous
cardiac output monitor with the patients placed in a standing position.
The patients were classified as pregnant women with hypertensive
disorders of pregnancy who delivered appropriate- and small-for-
gestational-age fe- tuses. Normotensive pregnant women with
an appropriate-for- gestational-age fetus at delivery were enrolled as
the control group. The possible impact of obesity (body mass index
30 kg/m2) on maternal hemodynamics was reassessed in the same
groups.
RESULTS: Maternal age, parity, body mass index, and blood pressure
were not significantly different between the hypertensive disorders of
pregnancy/appropriate-for-gestational-age and hypertensive disorders of
pregnancy/small-for-gestational-age groups. The mean uterine artery
pulsatility index was significantly higher in the hypertensive disorders of
pregnancy/small-for-gestational-age group. The cardiac output and car-
diac index were significantly lower in the hypertensive disorders of
pregnancy/small-for-gestational-age group (cardiac output 6.5 L/min,
cardiac index 3.6) than in the hypertensive disorders of pregnancy/
appropriate-for-gestational-age group (cardiac output 7.6 L/min, car-
diac index 3.9) but not between the hypertensive disorders of pregnancy/
appropriate-for-gestational-age and control groups (cardiac output 7.6 L/
min, cardiac index 4.0). Total vascular resistance was significantly
higher in the hypertensive disorders of pregnancy/small-for-gestational-
age group than in the hypertensive disorders of pregnancy/
appropriate-for-gestational-age group and the control group. All women
with hypertensive disorders of pregnancy showed signs of central arterial
dysfunction. The cardiovascular parameters were not influenced by
gestational age at the onset of hypertensive disorders of pregnancy, and
no difference was observed between the women with appropriate-for-
gestational-age fetuses affected by preeclampsia or by gestational hy-
pertension with appropriate-for-gestational-age fetuses. Women in the
obese/hypertensive disorders of pregnancy/appropriate-for-gestational-
age and obese/hypertensive disorders of pregnancy/small-for-
gestational-age groups showed a significant increase in cardiac output,
as well as significant changes in other parameters, compared with the
nonobese/hypertensive disorders of pregnancy/appropriate-for-
gestational-age and nonobese/hypertensive disorders of pregnancy/
small-for-gestational-age groups.
CONCLUSION: Significantly low cardiac output and high total vascular
resistance characterized the women with hypertensive disorders of
pregnancy associated with small for gestational age due to placental
insufficiency, independent of the gestational age at the onset of hyper-
tension. The cardiovascular parameters were not significantly different in
the women with appropriate-for-gestational-age or small-for-gestational-
age fetuses affected by preeclampsia or gestational hypertension.
These findings support the view that maternal hemodynamics may be
a candi- date diagnostic tool to identify hypertensive disorders in
pregnancies associated with small-for-gestational-age fetuses. This
additional tool matches other reported evidence provided by uterine
Doppler velocimetry, low vascular growth factors in the first trimester, and
placental pathology. Obesity is associated with a significantly higher
cardiac output and out- weighs other determinants of hemodynamics in
pregnancy; therefore, in future studies on hypertensive disorders, obesity
should be studied as an additional disease and not simply as a
demographic characteristic.
Key words: appropriate for gestational age, body mass index,
cardiac output, cardiovascular hemodynamics, eclampsia, hypertensive
disorders of pregnancy, obesity, preeclampsia, small for gestational age,
total vascular resistance

Introduction
Maternal blood pressure (BP) has been
used as a robust tool for diagnosing,
Cite this article as: Ferrazzi E, Stampalija T, Monasta L,
et al. Maternal hemodynamics: a method to classify
hypertensive disorders of pregnancy. Am J Obstet
Gynecol 2018;218:124.e1-11.
0002-9378/free
ª 2017 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2017.10.226
124.e1 American Journal of Obstetrics & Gynecology JANUARY 2018
classifying, and therapeutic targeting of
hypertensive disorders of pregnancy
1
(HDP).
Among HDP, preeclampsia (PE)
represents a huge burden to obstetrical
and neonatal outcome and long-term
outcome of women with PE in preg-
nancy: there are recent studies about
2
short-term cost of PE, the health
3
economic burden of PE, and evidence
that PE increases cardiovascular risk in
4
the fifth decade of life. Moreover,
recent studies have uncovered that
early treatment of critical BP
decreased
the risk of eclampsia and severe
5
maternal morbidity, and that the his-
tory of PE is associated with a risk of
coronary artery calcification 3 decades
6
later. In addition to these important
impacts of PE, a large retrospective
ajog.org OBSTETRICS Original Research
Original Research OBSTETRICS ajog.org
16
cohort of endothelia reviewed interroga phenotype with the 2015 maternal
study
7 cardiac l cell by Red- tion of of early- primary according medicine
conducted output dysfunctio man et maternal onset PE, placental to the unit of
and total n is the al
11
and cardiova which is phenotypes classificati Ziekenhuis
in 15
vascular common Staff et scular more that on of Oost-
hospi- tals
resistance result of al,
12
who hemody frequently characterize the Limburg
participati
(TVR). circulating showed namics associated HDP. Working (Genk,
ng in the
TVR is fac- tors how in HDP. with poor This Group on Belgium).
California
the result either In fact, placentation study High In this
Maternal oxidative
of many resulting in the and fetal aimed to Blood cohort,
Quality stressed
physiolog from early last growth examine Pressure women with
Care syncy-
ic reduced decade, restriction, the in singleton
Collaborat tiotrophob
factors, placental many whereas maternal Pregnancy pregnan-
ive on last
including perfusion studies maternal hemodynam . cies who
women oversecret
endotheli observed cardiac ics of a Additional were
with or from es
al that output prospec- prospectiv admitted
severe “maternal proteins
function, maternal appears to tive cohort e data for new-
intrapartu disorders that
as well as cardiac be according to were onset
m preexisting contribute
the target output is increased in the clinical gathered hypertensio
hypertensi . to the
of reduced the typical phenotypes (to date), n week
on pregnancy. pathogene
maternal in the phenotype that including >20 were
(systolic ” In sis of
inflamma typical of late- prioritize demograp consid- ered
BP >160 2006, with hypertensi
tory clinical onset PE,
13-
fetoplacenta hic, for
mm Hg or similar but on and
response 15
l clinical, inclusion,
diastolic updated organ which is
to more characteristi and
BP >105 in- lesions and enrolled
placental frequently cs, and unpublishe
mm Hg) terpretatio through by informed
and associated maternal d data,
proved ns, endothelia signed
metaboli with obesity as a such as
that these Borzycho l damage. consent.
preexisting proxy of uterine
women c wski et However, Approval of
cardiovascul metabolic artery
also had a dysfuncti al
10 early- the ethical
8 ar risk syndrome, Doppler
significant on. proposed onset PE committee
10,11, velocimetr
In that PE has an factors. rather than was
ly higher y and
pregnanc can extrinsic 14 the time at obtained
risk of body
y, develop in cause Consequ onset of before study
severe surface
different the (ie, poor ently, we HDP. onset (MEC
maternal area
morbidity placental presence placentati hypothesize (BSA), by ZOL
compared condition of a on), d that Ma retrieving reference:
to women s might normal whereas cardiovascu teri orig- inal 0
without damage size late-onset lar als measurem 8
the placenta PE has an dysfunction and ents from /
severe
maternal in women intrinsic al 0
hypertensi Me clinical
4
on. endotheli affected causeemi adaptation re- cords
tho 9
In all um, by crovillous to 17
ds forms. In ,
these making systemic overcrowd pregnancy
We addition, 0
studies BP this inflam- ingeas could be a we
placental analyzed 9
had been dysfuncti mation. more calculated
growth the original /
the key on the The powerful TVR
reaches its database of 0
classificati common placental diagnostic using an
functional a cohort of 5
on criteria. gateway pathology tool than establishe
11 women 0
Indeed, for that limit. the time at d
with ,
BP, HDP. In supports The the onset of formula.
13
gestational a
although 1996, this implicatio high BP to All n
hy-
easy to Ness and interpretati ns of these understand cases were d
Roberts
9 pertension
measure in on of PE studies the recruited 1
suggested (GH) or
all clinical has been could be different at the 0
that PE
settings, is more supported conditions fetal- /
altered reported in
the result recently by the associated 0
 ajog.org OBSTETRICS Original Research
6 superimp pre- (expressed l-age normalize
5 osed PE, viously in (SGA) d for the
). was reported, 1/100/s), group. BSA
17

HDP excluded. repeatable which The de- because

were Women method.
18- represents mograph the
defined with any
20
The the ic, cardiac
according to maternal impedance maximum clinical, index is
the criteria disease cardiograp acceleratio and sup-
of the or who hy pa- n of blood hemody posed to
National rameters flow in the namic correct
later
High Blood were the aorta.
21 findings the
develope
Pressure left In this of these cardiac
d HELLP
Education ventricular larger, 2 groups output for
syndrom
Program output and updated were the real
e were
Working aortic flow prospectiv then volume of
1 excluded
Group ; for from this parameters e cohort, compare distributio
the purposes study. . The left we d to a n of blood
of this Using ventricular identified control flow.
study, a output 2 group of The
chronic parameters homogeno women second
noninvas
hypertensio were the us groups with step of
ive
n, with or stroke of uneventf this
continuo
without volume pregnant ul analysis
us
cardiac (SV) (in women pregnanc was
output mL), heart affected ies. performed
monitor rate (HR) by HDP, The to
(NICCO in as defined first step compare
MO, beats/min, above, of this these 2
Software and classified study groups,
Version cardiac according was the
2.0; output in to the analysis
Medis L/min newborn and
Medizini (cardiac weight comparis
- sche output ¼ centile on of
Messtech HR SV). (above or the
nik The aortic below the cardio-
GmbH, flow 10th vascular
Ilmenau, parameters centile), indices
Germany were the according observed
), aortic to local in these
cardiovas velocity standards
2 2 groups
cular index 2 affected
to select
paramete (VI) by HDP
the
rs were (expressed accordin
following
obtained in g to their
2 groups:
through 1/1000/s), associati
(1) the
impedan which is on with
HDP/
ce equivalent AGA or
appropriat
cardiogra to the SGA
e-for-
phy with amplitude newborn
gestationa
the of the sys- s.
l-age
women tolic Cardiac
(AGA)
in a wave, and output
group; and
standing the aortic was also
(2) the
position, acceleratio analyzed
HDP/smal
accordin n index after it
l-for-
g to a (ACI) was
gestationa
Original Research OBSTETRICS ajog.org

TABLE 1
Maternal characteristics, laboratory results, and neonatal characteristics of hypertensive disorders of pregnancy/
appropriate for gestational age, hypertensive disorders of pregnancy/small-for-gestational-age, and control groups
ajog.org OBSTETRICS Original Research
P values for between-
Group group comparisons
HDP-AGA HDP-SGA HDP-AGA
Variable Control HDP-AGA HDP-SGA vs control vs control vs HDP-SGA
N 33 142 41
Maternal age, y 30 (27e33) 29 (26e32) 29 (27e32) .5 .4 .9
2
BMI, kg/m 23.3 (19.8e28.4) 24.9 (22.7e28.7) 24.0 (21.5e29.3) .2 .9 .2
Nulliparous 15 (45%) 36 (25%) 12 (29%) .03 .2 .7
þ5 þ1 þ0 þ3 þ3 þ4 a þ0 þ6 þ6 a
GA at examination 34 (32 e39 ) 37 (36 e38 ) 36 (32 e37 ) .06 1.0 .01a
Hemoglobin, g% 12.5 (11.4e12.8) 12.0 (11.3e12.9) 12.9 (12.2e13.9) .3 .04a .0006a
Thrombocyte 197 (156e240) 190 (158e225) 189 (160e223) 1.0 .7a .8a
count, 1000/mm3
Uric acid, mmol/L 4.52 (3.63e5.66)a 5.68 (4.84e6.58)a 6.34 (5.58e7.14)a .0000a .0000a .002a
24-h urine protein, mg 153 (117e179)a 359 (187e925)a 672 (334e2495)a .0000a .0000a .013a
Mean uterine artery PI 0.66 (0.53e0.83) 0.69 (0.57e0.87) 0.93 (0.71e1.16)a .4 .001a .0001a
GA at birth, wk 39þ1 (36þ4e40þ1) 38þ1 (36þ2e39þ3) 36þ0 (33þ4e38þ2)a .1 .003a .002a
Birthweight, g 3235 (2590e3545) 2992 (2645e3470) 2015 (1477e2450)a .4 .0000a .0000a
Male gender 20 (62.5%) 66 (46.5%) 23 (56.1%) .1 .6 .3
a a
Birthweight percentile 47.5 (22.5e65) 45 (25e70) 5 (2.5e7.5) .7 .0000 .0000a
Data are reported as median (interquartile range) or n (%) unless otherwise specified.
AGA, appropriate for gestational age; BMI, body mass index; GA, gestational age; HDP, hypertensive disorders of pregnancy; PI, pulsatility index; SGA, small for gestational age.
a
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons a ¼ 0.02.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.

including the same cardiac indices
observed in the early and late third
trimester, <34 and >34 weeks of gesta-
tion, to determine whether the step-1
results were biased by gestational age at
the time of examination in the affected
groups and the controls.
The third analytical step was per-
formed to compare the maternal
hemodynamic in patients affected
by GH or by PE delivered of AGA
newborns to analyze whether protein-
uria had any influence on maternal
hemodynamics.
The fourth analysis was performed on
the 2 HDP-AGA and HDP-SGA groups
to compare the subgroups of women
with a body mass index (BMI) >30 or
<30 at the time of examination. This
analysis was performed to estimate the
possible impact of obesity on maternal
hemodynamics in pregnant patients
affected by HDP.
The final analysis was made on
the entire cohort, which was then tradi-
tionally classified as early-onset PE, late-
onset PE, and GH.
1
The cardiovascular indices observed
in these 2 groups and in the control
group selected for this post hoc analysis
were statistically compared. We used
the Mann-Whitney rank-sum nonpara-
metric test or 2-tailed t tests, as appro-
priate, to compare continuous variables
between pairs of groups. Fisher exact 2-
tailed test was used to determine the
significance of association in 2 2 striction (IUGR) groups. The 3 groups
contingency tables. For statistical com-
parisons, the level of significance was set
at a ¼ 0.05. When >2 groups were
simultaneously compared, the Bonfer-
roni method was also used to assess
more stringent P values by dividing .05
by the number of comparisons. Unless
speci- fied, all data are reported as the
median (interquartile range [IQR])
or the
number (percentage) of women. All
statistical analyses were performed using
software (Stata/IC 14.1; StataCorp LP,
College Station, TX).
Results
The present updated cohort analyzed
216 cases under this different tentative
stratification of cases.
Table 1 summarizes the maternal
characteristics, laboratory results, and
neonatal outcomes of the control, HDP-
AGA, and HDP-intrauterine growth re-
were similar in terms of the maternal
age, BMI, and hemoglobin concentra-
tion. Note that maternal age, BMI, and
parity were not significantly different
between the groups.
Table 2 presents the cardiovascular
parameters for the control, HDP-AGA,
and HDP-IUGR groups. BP was not
significantly different between the
TABLE 2
Comparison of cardiovascular parameters in hypertensive disorders of pregnancy/appropriate for gestational
age, hypertensive disorders of pregnancy/small-for-gestational-age, and control groups
Group P values for between-group comparisons
HDP-AGA HDP-SGA HDP-AGA
Variable Control HDP-AGA HDP-SGA vs control vs control vs HDP-SGA
N 33 142 41
MAP, mm Hg 95.5 (88e107)a 112 (104e118) 110 (103e117) .0000a .0000a .6
Heart rate, beats/min 99 (91e108) 93 (87e105) 93 (82e101) .4 .09 .1
Stroke volume, mL 78 (68e88) 81.5 (65e95) 75 (60e90) .8 .3 .1
a a
Cardiac output, L/min 7.6 (7.0e8.4) 7.6 (6.2e8.9) 6.5 (6.0e7.7) .8 .007 .006a
Cardiac index 4.0 (3.8e4.4) 3.9 (3.4e4.5) 3.6 (3.3e4.0)a .1 .0004a .02a
e5 a a a a a
TVR, dynes/s/cm 1082 (905e1175) 1214 (1020e1451) 1399 (1198e1563) .002 .0000 .008a
VI, 1/1000/s 61 (54e76)a 46 (39e56) 49 (40e58) .0000a .0002a .5
2 a a a
ACI, 1/100/s 118 (93e147) 86 (72e116) 84 (67e124) .0001 .003 .9
Data are reported as median (interquartile range) unless otherwise specified.
ACI, acceleration index; AGA, appropriate for gestational age; HDP, hypertensive disorders of pregnancy; MAP, mean arterial pressure; SGA, small for gestational age; TVR, total vascular resistance;
VI, velocity index.
a
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.
HDP the and ACI gestational cardiovasc L/min (IQR The t output,
groups. cardiac values. age at ular 6.0-7.1) and median P and
Cardiac index Table 3 onset in parameter 3.6 (IQR values of r cardiac
output (cardiac shows the the third s of this 3.1-3.9), this i index were
was output cardiovasc trimester. subgroup respectively. subgroup n not
significant corrected ular A analysis. TVR was closely c significantl
ly lower for BSA) parameters subgroup With the 1400 matched i y different
in the in the in the 2 analysis excep- dynes/s/cm the median p in patients
e5 affected by
HDP- entire groups was tion of (IQR values of a
IUGR cohort of according conducted HR, none 1232-1569); the entire l early and
group HDP- to early for patients of the VI and ACI cohort of late PE
than in AGA and late with AGA cardiovasc were 48 1/ HDP-SGA f and GH
the HDP- women onset of fetuses with ular 1000/s (IQR patients, i compared
AGA was not the PE or of parameter 38-58), and albeit with n with those
group. significan hypertensi GH. s proved 84 (IQR 66- a different, d of the
TVR was tly ve disorder Maternal to be 121). smaller i control
significant different in HDP age, BMI, significant variance. n group. In
ly greater from that patients uterine ly higher Table 5 g fact, the
in the in the with AGA artery (5 shows the s classificati
HDP- control and SGA pulsatility beats/min highly The on of the
IUGR group; fetuses. index, and on significant cardiovas National
group however, None of normal average) impact cular High
than in it the birth- in women that paramete Blood
HDP-AGA remained cardio- weight with GH. obesity rs Pressure
and significan vascular centile were A had on observed Education
control tly parameters not similar cardiovas- in the Program
groups. greater were significantl subanalysis cular entire Working
1
The BSA than that influenced y different. was parameters cohort Group by
in the observed by The median performed , primarily classified definition
entire in the gestational for the on patients accordin does not
cohort of HDP- age at the patients with HDP- g to the take into
HDP- SGA cardiograph who had SGA. same account
AGA women. ic SGA Table 6 criteria maternal
women Compa examinatio fetuses and shows the as cardiovas-
(1.99 red with n differed PE (33 cardiovasc previousl cular
2
0.22 m ) the by only 1 patients) ular pa- y re- parameters
was women week, albeit or GH (8 rameters ported .
significantl proving a patients). of the on a
with
y greater signifi- cant The small entire smaller
normal
(P < .03) difference number of cohort 16
pregnanc cohort
than that the latter classified
ies, all for a confirme
in the cases did using the
women skewed d that
entire not allow same
with distribution 1 none of
cohort us to criteria
HDP of weeks at these
(nonobese perform a adopted
showed delivery in paramete
and obese) meaningfu from the
signs of patients first rs were
of HDP- with PE (29 l statistical significan
central reported
SGA weeks, IQR assess- tly
arterial study.
16
women 26-32; vs ment. The
hemodyn different
(1.90 30 weeks, cardiac
amic C among
0.16 m2) IQR output
dysfuncti early-
and 26-33) and o onset PE,
on, as
control (Supplemen cardiac in- m late-onset
women illus-
trated by tal Table). dex of PE- m PE, and
(1.89 Table 4 SGA e GH. SV,
2 their low
0.16 m ). patients
aortic VI shows the n cardiac
Note that were 6.5
TABLE 3
Comparison of cardiovascular parameters between hypertensive disorders of pregnancy groups, appropriate vs
small for gestational age; <34 and >34 weeks of gestation
HDP-AGA HDP-AGA HDP-SGA HDP-SGA
34 wk >34 wk P 34 wk >34 wk Pa
No. of patients 25 117 16 25
SBP, mm Hg 149 (139e164) 149 (139e160) .9 144 (132e154) 149 (138e157) .3
DBP, mm Hg 101 (93e102) 98 (94e105) .8 97 (92e105) 99 (95e100) .6
MAP, mm Hg 111 (105e118) 112 (104e118) 1.0 110 (102e117) 110 (107e115) .6
Heart rate, beats/min 98 (85e106) 93 (87e105) 1.0 93 (83e99) 93 (82e101) .7
Stroke volume, mL 74 (63e83) 83 (67e97) .2 76 (65e96) 74 (59e86) .4
Cardiac output, L/min 7.3 (6.0e8.9) 7.6 (6.3e8.9) .4 6.7 (6.0e7.7) 6.4 (6.0e7.7) .5
Cardiac index 3.9 (3.4e4.4) 3.8 (3.3e4.6) .5 3.7 (3.2e4.1) 3.5 (3.3e3.9) .6
e5
TVR, dynes/s/cm 1220 (1005e1678) 1214 (1026e1451) .9 1329 (1156e1608) 1400 (1223e1527) .6
VI, 1/1000/s 45 (37e58) 46 (39e56) .8 45 (36e58) 49 (41e61) .5
2
ACI (1/1000/S ) 83 (63e113) 86 (73e116) .5 77 (65e122) 86 (71e128) .4
Data are reported as median (interquartile range) unless otherwise specified.
ACI, acceleration index; AGA, appropriate for gestational age; DBP, diastolic blood pressure; HDP, hypertensive disorders of pregnancy; MAP, mean arterial pressure; SBP, systolic blood pressure;
SGA, small for gestational age; TVR, total vascular resistance; VI, velocity index.
a
P values were significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.
 When the entire cohort of patients patients with hypertensive disorders SGA fetuses (HDP-SGA) had highly
affected by HDP was grouped by prior- (according to the definition used in our significantly lower cardiac output than
itizing fetal growth, we observed that the study, only those with PE or GH) and those patients with hypertensive disor-
ders and normal fetuses (HDP-AGA).
Such a high cardiac output difference
TABLE 4 between groups was robust enough that
Comparison of cardiovascular parameters between preeclampsia and the cardiac index (cardiac output cor-
gestational hypertension appropriate-for-gestational-age groups rected for the body surface) remained
significantly lower in the HDP-SGA
PE-AGA GH-AGA P group, even if BSA was significantly
N 90 52 lower in the HDP-IUGR group than in
SBP, mm Hg 149 (139e164) 149 (137e160) .8 the HDP-AGA and control groups.
Similarly, highly significant higher
DBP, mm Hg 98 (94e103) 99 (93e105) .9
TVR was observed in patients
MAP, mm Hg 112 (105e118) 112 (104e118) .8 affected by HDP-SGA than in
Heart rate, beats/min 91 (84e104) 96 (89e110) .04a patients with HDP-AGA. Increased
TVR was paral- leled by significantly
Stroke volume, mL 82 (67e93) 80 (62e97) .8
lower values of VI and ACI, which
Cardiac output, mL/min 7.6 (6.2e8.9) 7.6 (6.2e9.1) .7 represented the ampli- tude of the
Cardiac index 3.9 (3.4e4.4) 3.9 (3.3e4.5) .8 systolic wave and the maximum
TVR, dynes/s/cm e5
1220 (1038e1487) 1158 (983e1440) .6 acceleration of blood flow in the aorta,
respectively, as they are computed by
VI, 1/1000/s 47 (39e56) 46 (39e57) .9
the noninvasive continuous cardiac
ACI 86 (73e118) 84 (66e116) .8 output monitor (NICCOMO).
Data are reported as median (interquartile range) unless otherwise specified. However, in HDP-SGA patients,
For maternal demographics and clinical data, see Supplemental Table. these lower values observed in the
ACI, acceleration index; AGA, appropriate for gestational age; DBP, diastolic blood pressure; GH, gestational hypertension; MAP, aorta were accompanied by a low
mean arterial pressure; PE, preeclampsia; SBP, systolic blood pressure; TVR, total vascular resistance; VI, velocity index. cardiac output and high TVR, which
a
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02. a is together determined a worse placental
reported for each group that proved to be significantly different.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018. perfusion.
These highly significant differences
in maternal cardiovascular
parameters
TABLE 5
Comparison of cardiovascular parameters between nonobese (body mass index <30) and obese (body mass index
‡30) women divided by hypertensive disorders of pregnancy, appropriate vs small for gestational age
Nonobese Obese Nonobese Obese
HDP-AGA HDP-AGA P HDP-SGA HDP-SGA P
No. of patients 112 25 32 9
BMI, kg/m2 24.1 (22.1e27.1)a 33.5 (31.7e37.3)a .0001a 23.4 (21.9e25.6) 31.2 (31.1e33.9)a .0001a
MAP, mm Hg 111 (104e118) 116 (107e125) .1 111 (104e115) 110 (103e122) .5
Heart rate, beats/min 92 (87e104) 104 (84e111) .09 93 (82e100) 94 (86e103) .4
a a
Stroke volume, mL 81 (63e92) 83 (71e105) .2 70 (58e80) 93 (88e99) .004a
Cardiac output, L/min 7.4 (6.1e8.7)a 8.3 (7.4e10.6)a .009a 6.3 (5.8e7.0)a 8.7 (8.3e9.1)a .0004a
a a
Cardiac index 3.9 (3.4e4.4) 3.9 (3.3e4.6) .8 3.5 (3.1e3.7) 4.2 (3.9e4.3) .005a
TVR, dynes/s/cme5 1223 (1036e1487) 1137 (917e1403) .1 1451 (1289e1622)a 1152 (1026e1248)a .0005a
VI, 1/1000/s 49 (40e58)a 38 (30e41)a .0001a 50 (41e63) 44 (38e49) .1
a a a a a
ACI 93 (77e127) 72 (53e80) .0001 100 (69e129) 71 (53e80) .04a
Data are reported as median (interquartile range) unless otherwise specified.
ACI, acceleration index; AGA, appropriate for gestational age; BMI, body mass index; HDP, hypertensive disorders of pregnancy; MAP, mean arterial pressure; SGA, small for gestational age;
TVR, total vascular resistance; VI, velocity index.
a
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.
were not its cardio- lost if PE mal 60% of the 48 20 in cardiovas with
determine impact vascular had been plasma uterine late-onset cular preterm
d by the on dysfunctio classified volume artery PE. The adap- PE appear
occurrence metabolis n in HDP, according to expansion Doppler BMI was tation of to develop
2
of m and we gestational with low velocimetri 23 kg/m cases in a high-
hypertensi the observed age at onset aldosteron c values in early- which resistance/
ve autonomi marked without e serum were onset PE PE was low-
disorders c differences consid- concentrat abnormal vs 28 associ- volume
28
<34 or nervous in all car- ering a ions vs 17% in kg/m
2
in ated with hemodyna
>34 weeks and diovascula possible have been late-onset late-onset IUGR. mic state
of gestation cardiovas r role of reported PE, and the PE. As we Other at
nor by the cular parameters maternal in women birthweight can see importan midgestati
hemo- with PE percentile t studies on.
15
presence or systems, between from the
dynamics in asso- have Again, the
absence of it should the HDP- was 18 12 weight
the cross- ciated investi- study by
PE with be treated AGA and vs centile at
talk with poor Melchiorre
AGA as such HDP-SGA birth, gated the
between the fetal 15
fetuses or in groups. uterine complex et al, as
developing growth.
SGA biological Such Doppler cardiac well as the
placenta Our
fetuses. studies important and dysfuncti study by
and findings
As and differences maternal on and Valensise
maternal align with altered 13
expected, possibly would the BMI, the et al
obesity in clinical have been car- myocardi discussed
interpre- temporal
played a cohorts. diovascular al above,
23 tation of classi-
signifi- condition. remodeli studied 18
data fication
cant role, Interpre An ng that cases of
reported adopted
both in association affects early-onset
tation in an early by that
HDP-AGA between 40% of PE in
of the study by study,
women
and HDP- birthweight
findings Valensise mixed
and vascular who
SGA, in in HDP 13 different
resistance et al. In develop
changing w phenotype
was first fact, they PE at
maternal i observed s in terms
reported in term,
29
car- t 1991 by that as of feto-
diovascular and one
h Easterling early as placental
third of
parameters 24
24 weeks growth
et al. A women
into high S direct of and who
cardiac G relationship gestation, maternal develop
output A between cardiac risk of PE,
normal In the birthweight output metabolic regardles
peripheral present and was lower syndrome. s of
resistance, analysis, maternal and TVR Unfortunat gestation,
with an in which cardiac was ely, when demonstr
even we hy- output had higher in the ated
lower pothesize been more women temporal similar
amplitude d a recently who later classificati evidence
of the possible reported in developed on is of left
systolic women early PE adopted, ventricul
associati
wave and with one ar
on be- 25 than in
maximum tween IUGR and women misses the hypertro
26
acceleratio placental PE. who chance to phic
n of blood insufficie Moreover, developed investigate concentri
flow. In ncy with abnormal late PE. among c
fact, fetal central In that late-onset remodeli
obesity is a arterial reported PE cases ng.
growth
disease per hemodyna cohort the However,
restrictio 27
se, and n and mics and with early- possible only
because of subopti- onset PE, different women
maternal
TABLE 6
Cardiovascular parameters of entire cohort classified according to early- and late-onset preeclampsia and
gestational hypertension
Control Early PE Late PE GH P
N 33 39 84 60
SBP, mm Hg 132 (119e144)a 149 (135e158)b 149 (138e163)b 149 (137e160)b .0000a
DBP, mm Hg 85 (78e95)a 100 (92e104)b 98 (94e104)b 98 (92e105)b .0000a
MAP, mm Hg 96 (87e107)a 111 (103e117)b 112 (105e119)b 111 (104e118)b .0000a
a b
Heart rate, beats/min 99 (88e108) 93 (85e104) 90 (84e103) 96 (89e111) .02a
Stroke volume, mL 78 (68e89) 75 (63e88) 82 (65e94) 81 (61e96) .8
Cardiac output, L/min 7.6 (6.9e8.4) 6.9 (6.0e8.9) 7.2 (6.1e8.5) 7.6 (6.1e8.9) .4
Cardiac index 4.0 (3.7e4.5) 3.7 (3.3e4.4) 3.8 (3.4e4.3) 3.9 (3.4e4.5) .08
e5 a b b b
TVR, dynes/s/cm 1082 (898e1176) 1276 (1043e1621) 1246 (1062e1501) 1158 (1011e1436) .0009a
a b b b
VI, 1/1000/s 61 (54e76) 45 (36e58) 48 (39e57) 47 (39e58) .0000a
ACI, 1/100/s2 118 (91e149)a 80 (64e119)b 88 (73e121)b 84 (70e126)b .0009a
Data are reported as median (interquartile range) unless otherwise specified.
Analysis adjusted for multiple comparisons. Kruskal-Wallis test was
adopted.
ACI, acceleration index; DBP, diastolic blood pressure; GH, gestational hypertension; MAP, mean arterial pressure; PE, preeclampsia; SBP, systolic blood pressure; TVR, total vascular resistance;
VI, velocity index.
a
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02; b Significant difference compared to control group.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.
 32
women on and study by a Interpreta kidneys cardiac correction including s
who proteinur simplistic tion of or the output was of cardiac the Pregnancie
delivered ia, does but the release of much more output for amnio- s
babies not effective findings leptin, an than 0.1 BSA in tic fluid, associated
with a consider associ- in HDP aldosteron L/min per 1 obese receives with HDP
median either the ation of e agonist, kg/m
2
(1 pregnant between differ from
a
birthweigh different hypertensi from BMI U), as women. 450
27,36
- normal
n adipocytes
t percentile placental ve expected as Despite 830 pregnancie
d 34
of 4.7 pathologi disorders . a simple the mL/min.
3
s in terms
(IQR 2-7). es that with a In this direct effect tremendou 7,38 of
o Until
Thanks cause a robust study, of s abnormal
b difference
adequate
to this similar classificati despite its increasing cardiovasc
e hemody-
backgroun oxidative on of low preva- BMI.
35 in tissue ular
s namic
d informa- stress of normal or lence, we These perfu- sion hemody-
i models
tion, it is the restricted tried to findings between namics.
t are
not syncytiot fetal analyze challenge adipose Our
y impleme
difficult to rophobla growth. the impact the tissue and findings
Nonpregna nted, the
agree that st early of mechanistic the suggest
nt obese cardiac
“it is in maternal fetoplacent that
individuals output
certainly gestation obesity on al unit, women
typically value
plausible due to cardiovasc some
have high represent with HDP
that the shallow ular authors do
cardiac s the car- and SGA
placenta tropho- function correct
output, diac fetuses
cau- ses blastic in cardiac
mainly due strain and those
PE and invasion pregnant output for
to a large 15,29 and with HDP
IUGR in (as circulating women BSA adaptatio and AGA
the indicated 31 with HDP. and
volume n better fetuses
minority by low We found calculate
and a low than have
23 placental that the cardiac
of cases.” TVR, indices different
growth which cardiac index.
However, derived hemodyna
factor results from output Based on
it is from mic
and high a shift of increased the above
difficult to nonpregn dysfunctio
uterine noncirculati by reported
imagine ant ns
Doppler ng stored approxima findings,
35
that women.
pulsatilit splanchnic tely 0.9 we
fetoplacent
24 venous L/min calculated
al growth y index C
and fetal blood into both in that 5 kg of
restriction
women
l
stops its growth the fat mass
with HDP- i
decisive restrictio circulation receives
by AGA and n
cross-talk n), and 250
increased 2.4 L/min mL/min of
i
with the later in
central in women blood at c
maternal gestation
sympathetic with rest and a
cardiovasc due to 32
activity HDP- possibly l
ular villi
and from SGA. The less in
system at overcrow
11,30 increased average obese i
34 weeks ding, BMI
aldosterone pregnant m
of nor the 33 difference
gestation activity. women p
possible in the 2
The latter with
and ceases different groups l
condition dysfunctio
its role. By maternal might was 9.4 i
definition, nal leaking
cardiovas depend on and 7.8 c
the present endotheliu
cular visceral 2 a
kg/m , m,
classificatio performa obesity- t
respective whereas a
n, which is nce that related i
ly. The 5 kg
based on we compressio observed fetoplacent o
onset of observed n of the increase in al unit, n
hypertensi in this
 performance should be considered
FIGURE
when different antihypertensive drugs
Simplified schematic presentation of type-specific hemodynamics
are un- der scrutiny to treat moderate
to severe forms of hypertension in
39
pregnancy.

Research
implication
Differences in maternal cardiovascular
parameter matches other evidences
provided by uterine Doppler velocim-
5
etry, low vascular growth factors in
24
the first trimester, and placental
25
pathology. Future studies on these
predictors and markers of HDP should
consider adding maternal
cardiovascular parameters in addition
to simple peripheral arterial BP.
Obesity is associ- ated with higher
cardiac output and relatively reduced
TVR, as we observed in this study, as
well as with significant increase in left
ventricular mass as observed by cardiac
35
magnetic resonance imaging. It also
significantly outweighs other
A, nonpregnant state; B, normal pregnancy; C, hypertensive disorders of pregnancy (HDP) and determinants of hemodynamics in
intrauterine growth restriction (IUGR); and D, HDP-appropriate for gestational age (AGA) or even pregnancy and should be studied as an
large for gestational age. In nonpregnant state, blood flow to uterine arteries is negligible; at
additional disease and not as a simply
mid- pregnancy, it is 12% of whole cardiac output.37,38 Dimension of bellow represents dimension
demographic characteristic.
of left ventricle beating at given rate, with certain stroke volume (SV) with each blow, at given
heart rate (HR), tube diameter, and curvature (smooth ¼ low total vascular resistance [TVR]; Both conditions focused on in our
steep angle ¼ high TVR) represent TVR; balloon content represents cardiac output (cardiac output study represent a significant risk factor
¼ SV HR). Blood pressure (BP) inside tubes is product of cardiac output and TVR (BP ¼ [f] for cardiovascular disease (CVD) later
cardiac output TVR). Blue vessels are veins and their dimension represents plasma volume in life. Notably, in the presence of 3 or 4
relocated in capacitance vessels and in splanchnic venous system. As compared to A, risk factors for metabolic syndrome,
nonpregnant state, B, normal preg- nancy induces increase in SV and cardiac output. These including obesity, the adjusted hazard
early adaptations are simultaneous with major reduction of TVR that results in lower BP.47 In ratio for CVD later in life might
parallel, plasma volume increases by 1.2 L at 28 weeks of gestation,49 with one fourth of it increase by up to 10 times compared to
relocated in splanchnic venous system.21 Suboptimal plasma expansion in pregnancy was 40
unaf- fected pregnancies. PE and SGA
42
observed in pregnancies complicated by preeclampsia and fetal growth restriction. In C, HDP- too are independent risk factors for
IUGR, SV, HR, and cardiac output are lower than that in B, normal pregnancy. TVR is much CVD later in life; the 2 risk factors
higher than in both A and B, resulting in higher BP values13-15,26 and plasma volume is lower together, PE with SGA, increase the
than in normal pregnancies.38 In D, HDP-AGA, reported hemodynamic findings are controversial risk of CVD as much as 8-fold.
41
(see text for discussion). SV and cardiac output are similar or higher, and TVR similar or higher than
However, the respective
in B, normal pregnancy. In reported cohorts, combination of 2 factors (TVR and cardiac output)
results in higher BP. Under physiologic conditions, these fundamentally different states are pathophysiologies of these 2 different
influenced by many other variables, such as blood viscosity, anatomic and functional vascular phenotypes of placental damage and
wall integrity, and ratio between lean and fat mass. cardiovascular dysfunction appear to be
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol totally different, and it is likely that
2018. different preventive and therapeutic
42
strategies should be employed before,
during, and after pregnancy, as well as
43
later in life. These problems should be
investigated by future longitudinal
studies beginning with the early first
(Figure) and should be examined for hospital monitoring and major for these ex- aminations, recent studies
their cardiovascular performance when antihy- pertensive treatment. As cover a wide
maternal or fetal condition require in- regards the proper technique to adopt
spectrum of noninvasive technologies. trimester or even from the
We believe that, beyond screening preconcep- tion phase to the
tests, this diagnostic interrogation of postpregnancy long- term follow-up.
maternal cardiovascular system should
be performed by cardiologists. PE obvi- Strengths and
ously remains a more serious disease limitations
than GH, yet maternal cardiovascular The major limitation of this study is
that the only assessment of in utero
growth
was the value be- bias in pathology Group on health care eclampsia and 1 2014;35:S26-
High severe 3 31.
birthweigh tween the terms of and fetal system. Am
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al growth given the this pregnancy Pressure
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4 the BSA 8 . pre-
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and RR, Sep -82. charity
dynamic - 6 3 Stampalija)
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is leptin the L, The authors
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7 Shave R, (Dr Monasta),
0 Relevance of FK, 1 Drongelen J, Correspondi
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1 hemody- Spaanderman . Spaanderma ng author:
4 Cardiac Ricovero e
6 3 namics in MEA. 44. Marconi n MEA. Enrico
output and Cura a
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3 Scientifico
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SUPPLEMENTAL TABLE
Comparison of maternal demographics and clinical data between preeclampsia and gestational hypertension
appropriate-for-gestational-age groups
PE-AGA GH-AGA P
N 90 52
Maternal age, y 29 (26e32) 30 (26e33) .3
2
BMI, kg/m 24.2 (22.6e28.3) 26.9 (23.1e36.6) .08
GA at examination 37.0 (33.7e38.3) 38.0 (36.9e39.1) .0009a
Hemoglobin, g% 12.0 (11.0e12.7) 12.0 (11.7e13.2) .2
3
Thrombocyte count, 1000/mm 177 (152e208) 205 (188e244) .002a
Uric acid, mmol/L 5.8 (5.0e6.7) 5.5 (4.7e6.2) .04a
24-h urine protein, mg 756 (373e1473) 169 (131e206) .0000a
Mean uterine artery PI 0.73 (0.60e0.92) 0.62 (0.52e0.84) .06
GA at birth, wk 37.4 (34.6e38.7) 39.1 (38.3e40.0) .0000a
Birthweight, g 2858 (2179e3271) 3248 (2974e3668) .0000a
Birthweight percentile 40 (25e63) 49 (26e84) .2
Data are reported as median (interquartile range) unless otherwise specified.
AGA, appropriate for gestational age; BMI, body mass index; GA, gestational age; GH, gestational hypertension; PE, preeclampsia; PI, pulsatility index.
a
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02.
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.