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Original Research ajog.


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

Introduction economic burden of PE,3 and evidence

Maternal blood pressure (BP) has been that PE increases cardiovascular risk in
used as a robust tool for diagnosing, classifying, and therapeutic targeting of the fifth decade of life.4 Moreover,
hypertensive disorders of pregnancy recent studies have uncovered that
(HDP).1 early treatment of critical BP decreased
Cite this article as: Ferrazzi E, Stampalija T, Monasta L,
et al. Maternal hemodynamics: a method to classify
Among HDP, preeclampsia (PE) the risk of eclampsia and severe
hypertensive disorders of pregnancy. Am J Obstet represents a huge burden to obstetrical maternal morbidity,5 and that the his-
Gynecol 2018;218:124.e1-11. and neonatal outcome and long-term tory of PE is associated with a risk of
outcome of women with PE in preg- coronary artery calcification 3 decades
ª 2017 Elsevier Inc. All rights reserved. nancy: there are recent studies about later.6 In addition to these important
https://doi.org/10.1016/j.ajog.2017.10.226 short-term cost of PE,2 the health impacts of PE, a large retrospective

124.e1 American Journal of Obstetrics & Gynecology JANUARY 2018

ajog.org OBSTETRICS Original Research

cohort study7 conducted in 15 hospi- phenotype of early-onset PE, which is superimposed PE, was excluded.
tals participating in the California more frequently associated with poor Women with any maternal disease or
Maternal Quality Care Collaborative placentation and fetal growth restriction, who later developed HELLP syndrome
on women with severe intrapartum whereas maternal cardiac output appears were excluded from this study.
hypertension (systolic BP >160 mm to be increased in the typical phenotype Using a noninvasive continuous
Hg or diastolic BP >105 mm Hg) of late-onset PE,13-15 which is more cardiac output monitor (NICCOMO,
proved that these women also had a frequently associated with preexisting Software Version 2.0; Medis Medizini-
significantly higher risk of severe cardiovascular risk factors.10,11,14 sche Messtechnik GmbH, Ilmenau,
maternal morbidity compared to Consequently, we hypothesized that Germany), cardiovascular parameters
women without severe hypertension. cardiovascular dysfunctional adaptation were obtained through impedance
In all these studies BP had been the to pregnancy could be a more powerful cardiography with the women in a
key classification criteria. Indeed, BP, diagnostic tool than the time at the onset standing position, according to a pre-
although easy to measure in all clinical of high BP to understand the different viously reported, repeatable method.18-
settings, is the result of cardiac output conditions associated with the primary The impedance cardiography pa-
and total vascular resistance (TVR). TVR placental phenotypes that characterize rameters were the left ventricular
is the result of many physiologic factors, HDP. output and aortic flow parameters. The
including endothelial function, as well as This study aimed to examine the left ventricular output parameters were
the target of maternal inflammatory maternal hemodynamics of a prospec- the stroke volume (SV) (in mL), heart
response to placental and metabolic tive cohort according to the clinical rate (HR) in beats/min, and cardiac
dysfunction.8 phenotypes that prioritize fetoplacental output in L/min (cardiac output ¼
In pregnancy, different placental characteristics, and maternal obesity as a HR  SV). The aortic flow parameters
conditions might damage the maternal proxy of metabolic syndrome, rather were the aortic velocity index (VI)
endothelium, making this dysfunction than the time at onset of HDP. (expressed in 1/1000/s), which is
the common gateway for HDP. In equivalent to the amplitude of the sys-
1996, Ness and Roberts9 suggested that Materials and Methods tolic wave, and the aortic acceleration
altered endothelial cell dysfunction is We analyzed the original database of a index (ACI) (expressed in 1/100/s),
the common result of circulating fac- cohort of women with gestational hy- which represents the maximum
tors either resulting from early reduced pertension (GH) or PE reported in acceleration of blood flow in the aorta.21
placental perfusion or from “maternal 201516 according to the classification of In this larger, updated prospective
disorders preexisting. pregnancy.” In the Working Group on High Blood cohort, we identified 2 homogenous
2006, with similar but updated in- Pressure in Pregnancy. Additional groups of pregnant women affected by
terpretations, Borzychowski et al10 prospective data were gathered (to HDP, as defined above, classified
proposed that PE can develop in the date), including demographic, clinical, according to the newborn weight centile
presence of a normal size placenta in and unpublished data, such as uterine (above or below the 10th centile),
women affected by systemic inflam- artery Doppler velocimetry and body according to local standards22 to select
mation. The placental pathology that surface area (BSA), by retrieving orig- the following 2 groups: (1) the HDP/
supports this interpretation of PE has inal measurements from clinical re- appropriate-for-gestational-age (AGA)
been more recently reviewed by Red- cords forms.17 In addition, we group; and (2) the HDP/small-for-
man et al11 and Staff et al,12 who calculated TVR using an established gestational-age (SGA) group. The de-
showed how oxidative stressed syncy- formula.13 mographic, clinical, and hemodynamic
tiotrophoblast oversecretes proteins All cases were recruited at the fetal- findings of these 2 groups were then
that contribute to the pathogenesis of maternal medicine unit of Ziekenhuis compared to a control group of women
hypertension and organ lesions Oost-Limburg (Genk, Belgium). In this with uneventful pregnancies.
through endothelial damage. However, cohort, women with singleton pregnan- The first step of this study was the
early-onset PE has an extrinsic cies who were admitted for new-onset analysis and comparison of the cardio-
cause (ie, poor placentation), hypertension week >20 were consid- vascular indices observed in these 2
whereas late-onset PE has an intrinsic ered for inclusion, and enrolled by groups affected by HDP according to
causeemicrovillous overcrowdingeas informed signed consent. Approval of their association with AGA or SGA
placental growth reaches its functional the ethical committee was obtained newborns. Cardiac output was also
limit.11 before study onset (MEC ZOL reference: analyzed after it was normalized for the
The implications of these studies could 08/049, 09/050, and 10/065). BSA17 because the cardiac index is sup-
be supported by the interrogation of HDP were defined according to the posed to correct the cardiac output for
maternal cardiovascular hemodynamics criteria of the National High Blood the real volume of distribution of blood
in HDP. In fact, in the last decade, many Pressure Education Program Working flow.
studies observed that maternal cardiac Group1; for the purposes of this study, The second step of this analysis was
output is reduced in the typical clinical chronic hypertension, with or without performed to compare these 2 groups,

JANUARY 2018 American Journal of Obstetrics & Gynecology 124.e2

Original Research OBSTETRICS ajog.org

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
P values for between-group
Group comparisons
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
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
GA at examination 34þ5 (32þ1e39þ0) 37þ3 (36þ3e38þ4)a 36þ0 (32þ6e37þ6) .06 1.0a .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
a a
Birthweight, g 3235 (2590e3545) 2992 (2645e3470) 2015 (1477e2450) .4 .0000 .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.
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 The final analysis was made on number (percentage) of women. All
observed in the early and late third the entire cohort, which was then tradi- statistical analyses were performed using
trimester, <34 and >34 weeks of gesta- tionally classified as early-onset PE, late- software (Stata/IC 14.1; StataCorp LP,
tion, to determine whether the step-1 onset PE, and GH.1 College Station, TX).
results were biased by gestational age at The cardiovascular indices observed
the time of examination in the affected in these 2 groups and in the control Results
groups and the controls. group selected for this post hoc analysis The present updated cohort analyzed
The third analytical step was per- were statistically compared. We used the 216 cases under this different tentative
formed to compare the maternal Mann-Whitney rank-sum nonpara- stratification of cases.
hemodynamic in patients affected metric test or 2-tailed t tests, as appro- Table 1 summarizes the maternal
by GH or by PE delivered of AGA priate, to compare continuous variables characteristics, laboratory results, and
newborns to analyze whether protein- between pairs of groups. Fisher exact 2- neonatal outcomes of the control, HDP-
uria had any influence on maternal tailed test was used to determine the AGA, and HDP-intrauterine growth re-
hemodynamics. significance of association in 2  2 striction (IUGR) groups. The 3 groups
The fourth analysis was performed on contingency tables. For statistical com- were similar in terms of the maternal
the 2 HDP-AGA and HDP-SGA groups parisons, the level of significance was set age, BMI, and hemoglobin concentra-
to compare the subgroups of women at a ¼ 0.05. When >2 groups were tion. Note that maternal age, BMI, and
with a body mass index (BMI) >30 or simultaneously compared, the Bonfer- parity were not significantly different
<30 at the time of examination. This roni method was also used to assess more between the groups.
analysis was performed to estimate the stringent P values by dividing .05 by the Table 2 presents the cardiovascular
possible impact of obesity on maternal number of comparisons. Unless speci- parameters for the control, HDP-AGA,
hemodynamics in pregnant patients fied, all data are reported as the median and HDP-IUGR groups. BP was not
affected by HDP. (interquartile range [IQR]) or the significantly different between the

124.e3 American Journal of Obstetrics & Gynecology JANUARY 2018

ajog.org OBSTETRICS Original Research

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
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.
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 groups. Cardiac output was gestational age at onset in the third The median values of this subgroup closely
significantly lower in the HDP-IUGR trimester. matched the median values of the entire
group than in the HDP-AGA group. A subgroup analysis was conducted cohort of HDP-SGA patients, albeit with a
TVR was significantly greater in the for patients with AGA fetuses with PE or different, smaller variance.
HDP-IUGR group than in HDP-AGA of GH. Maternal age, BMI, uterine artery Table 5 shows the highly significant
and control groups. pulsatility index, and normal birth- impact that obesity had on cardiovas-
The BSA in the entire cohort of HDP- weight centile were not significantly cular parameters, primarily on patients
AGA women (1.99  0.22 m2) was different. The median gestational age at with HDP-SGA.
significantly greater (P < .03) than that the cardiographic examination differed Table 6 shows the cardiovascular pa-
in the entire cohort (nonobese and by only 1 week, albeit proving a signifi- rameters of the entire cohort classified
obese) of HDP-SGA women (1.90  cant difference for a skewed distribution using the same criteria1 adopted from
0.16 m2) and control women (1.89  of weeks at delivery in patients with PE the first reported study.16
0.16 m2). Note that the cardiac index (29 weeks, IQR 26-32; vs 30 weeks, IQR
(cardiac output corrected for BSA) in 26-33) (Supplemental Table). Table 4 Comment
the entire cohort of HDP-AGA women shows the cardiovascular parameters of Principal findings
was not significantly different from that this subgroup analysis. With the excep- The cardiovascular parameters observed
in the control group; however, it tion of HR, none of the cardiovascular in the entire cohort classified according
remained significantly greater than that parameters proved to be significantly to the same criteria as previously re-
observed in the HDP-SGA women. higher (5 beats/min on average) in ported on a smaller cohort16 confirmed
Compared with the women with women with GH. that none of these parameters were
normal pregnancies, all women with A similar subanalysis was performed for significantly different among early-onset
HDP showed signs of central arterial the patients who had SGA fetuses and PE PE, late-onset PE, and GH. SV, cardiac
hemodynamic dysfunction, as illus- (33 patients) or GH (8 patients). The small output, and cardiac index were not
trated by their low aortic VI and ACI number of the latter cases did not allow us significantly different in patients affected
values. to perform a meaningful statistical assess- by early and late PE and GH compared
Table 3 shows the cardiovascular ment. The cardiac output and cardiac in- with those of the control group. In fact,
parameters in the 2 groups according to dex of PE-SGA patients were 6.5 L/min the classification of the National High
early and late onset of the hypertensive (IQR 6.0-7.1) and 3.6 (IQR 3.1-3.9), Blood Pressure Education Program
disorder in HDP patients with AGA respectively. TVR was 1400 dynes/s/cme5 Working Group1 by definition does not
and SGA fetuses. None of the cardio- (IQR 1232-1569); VI and ACI were 48 1/ take into account maternal cardiovas-
vascular parameters were influenced by 1000/s (IQR 38-58), and 84 (IQR 66-121). cular parameters.

JANUARY 2018 American Journal of Obstetrics & Gynecology 124.e4

Original Research OBSTETRICS ajog.org

Comparison of cardiovascular parameters between hypertensive disorders of pregnancy groups, appropriate vs small
for gestational age; <34 and >34 weeks of gestation
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
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
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.
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 TVR
DBP, mm Hg 98 (94e103) 99 (93e105) .9
was observed in patients affected by
MAP, mm Hg 112 (105e118) 112 (104e118) .8 HDP-SGA than in patients with
Heart rate, beats/min 91 (84e104) 96 (89e110) .04a HDP-AGA. Increased TVR was paral-
Stroke volume, mL 82 (67e93) 80 (62e97) .8 leled by significantly lower values of VI
and ACI, which represented the ampli-
Cardiac output, mL/min 7.6 (6.2e8.9) 7.6 (6.2e9.1) .7
tude of the systolic wave and the
Cardiac index 3.9 (3.4e4.4) 3.9 (3.3e4.5) .8 maximum acceleration of blood flow in
e5 the aorta, respectively, as they are
TVR, dynes/s/cm 1220 (1038e1487) 1158 (983e1440) .6
VI, 1/1000/s 47 (39e56) 46 (39e57) .9
computed by the noninvasive continuous
cardiac output monitor (NICCOMO).
ACI 86 (73e118) 84 (66e116) .8 However, in HDP-SGA patients, these
Data are reported as median (interquartile range) unless otherwise specified. lower values observed in the aorta were
For maternal demographics and clinical data, see Supplemental Table. accompanied by a low cardiac output and
ACI, acceleration index; AGA, appropriate for gestational age; DBP, diastolic blood pressure; GH, gestational hypertension; MAP, high TVR, which together determined a
mean arterial pressure; PE, preeclampsia; SBP, systolic blood pressure; TVR, total vascular resistance; VI, velocity index.
worse placental perfusion.
P values significant at level of a ¼ 0.05, after applying Bonferroni correction for multiple comparisons, a ¼ 0.02. a is reported
for each group that proved to be significantly different. These highly significant differences in
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018. maternal cardiovascular parameters

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ajog.org OBSTETRICS Original Research

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
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.
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 determined by the occurrence lost if PE had been classified according to 48  20 in late-onset PE. The BMI was
of hypertensive disorders <34 or >34 gestational age at onset without consid- 23 kg/m2 in early-onset PE vs 28 kg/m2
weeks of gestation nor by the presence or ering a possible role of maternal hemo- in late-onset PE. As we can see from the
absence of PE with AGA fetuses or SGA dynamics in the cross-talk between the weight centile at birth, uterine Doppler
fetuses. developing placenta and maternal car- and maternal BMI, the temporal classi-
As expected, obesity played a signifi- diovascular condition.23 fication adopted by that study, mixed
cant role, both in HDP-AGA and An association between birthweight different phenotypes in terms of feto-
HDP-SGA, in changing maternal car- and vascular resistance was first reported placental growth and maternal risk of
diovascular parameters into high cardiac in 1991 by Easterling et al.24 A direct metabolic syndrome. Unfortunately,
output normal peripheral resistance, relationship between birthweight and when the temporal classification is
with an even lower amplitude of the maternal cardiac output had been more adopted, one misses the chance to
systolic wave and maximum acceleration recently reported in women with IUGR25 investigate among late-onset PE cases the
of blood flow. In fact, obesity is a disease and PE.26 Moreover, abnormal central possible different cardiovascular adap-
per se, and because of its impact on arterial hemodynamics27 and subopti- tation of cases in which PE was associ-
metabolism and the autonomic nervous mal plasma volume expansion with low ated with IUGR.
and cardiovascular systems, it should be aldosterone serum concentrations28 have Other important studies have investi-
treated as such in biological studies and been reported in women with PE asso- gated the complex cardiac dysfunction
possibly in clinical cohorts. ciated with poor fetal growth. and altered myocardial remodeling that
Our findings align with the interpre- affects 40% of women who develop PE at
Interpretation of the findings in HDP tation of data reported in an early study term,29 and one third of women who
with SGA by Valensise et al.13 In fact, they observed develop PE, regardless of gestation,
In the present analysis, in which we hy- that as early as 24 weeks of gestation, demonstrated similar evidence of left
pothesized a possible association be- cardiac output was lower and TVR was ventricular hypertrophic concentric
tween placental insufficiency with fetal higher in women who later developed remodeling. However, only women with
growth restriction and maternal cardio- early PE than in women who developed preterm PE appear to develop a high-
vascular dysfunction in HDP, we late PE. In that reported cohort with resistance/low-volume hemodynamic
observed marked differences in all car- early-onset PE, 60% of the uterine artery state at midgestation.15 Again, the study
diovascular parameters between the Doppler velocimetric values were by Melchiorre et al,15 as well as the study
HDP-AGA and HDP-SGA groups. Such abnormal vs 17% in late-onset PE, and by Valensise et al13 discussed above,
important differences would have been the birthweight percentile was 18  12 vs studied 18 cases of early-onset PE in

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Cardiovascular parameters of entire cohort classified according to early- and late-onset preeclampsia and gestational
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.
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.

women who delivered babies with a Interpretation of the findings in HDP correction of cardiac output for BSA in
median birthweight percentile of 4.7 and obesity obese pregnant women. Despite the
(IQR 2-7). Nonpregnant obese individuals typically tremendous difference in tissue perfu-
Thanks to this background informa- have high cardiac output, mainly due to a sion between adipose tissue and the
tion, it is not difficult to agree that “it is large circulating volume31 and a low fetoplacental unit, some authors do
certainly plausible that the placenta cau- TVR, which results from a shift of correct cardiac output for BSA15,29 and
ses PE and IUGR in the minority of noncirculating stored splanchnic venous calculate the cardiac index. Based on the
cases.”23 However, it is difficult to imagine blood into the circulation by increased above reported findings,35 we calculated
that fetoplacental growth restriction stops central sympathetic activity32 and from that 5 kg of fat mass receives 250 mL/min
its decisive cross-talk with the maternal increased aldosterone activity.33 The of blood at rest and possibly less in obese
cardiovascular system at 34 weeks of latter condition might depend on pregnant women with dysfunctional
gestation and ceases its role. By definition, visceral obesity-related compression of leaking endothelium, whereas a 5 kg
the present classification, which is based the kidneys32 or the release of leptin, an fetoplacental unit, including the amnio-
on onset of hypertension and proteinuria, aldosterone agonist, from adipocytes.34 tic fluid, receives between 45027,36-830
does not consider either the different In this study, despite its low preva- mL/min.37,38 Until adequate hemody-
placental pathologies that cause a similar lence, we tried to analyze the impact of namic models are implemented, the
oxidative stress of the syncytiotrophoblast maternal obesity on cardiovascular cardiac output value represents the car-
early in gestation due to shallow tropho- function in pregnant women with HDP. diac strain and adaptation better than
blastic invasion (as indicated by low We found that cardiac output increased indices derived from nonpregnant
placental growth factor and high uterine by approximately 0.9 L/min both in women.
Doppler pulsatility index24 and fetal women with HDP-AGA and 2.4 L/min in
growth restriction), and later in gestation women with HDP-SGA. The average Clinical implications
due to villi overcrowding,11,30 nor the BMI difference in the 2 groups was 9.4 Pregnancies associated with HDP differ
possible different maternal cardiovascular and 7.8 kg/m2, respectively. The from normal pregnancies in terms of
performance that we observed in this observed increase in cardiac output was abnormal cardiovascular hemody-
study by a simplistic but effective associ- much more than 0.1 L/min per 1 kg/m2 namics. Our findings suggest that
ation of hypertensive disorders with a (1 BMI U), as expected as a simple direct women with HDP and SGA fetuses and
robust classification of normal or effect of increasing BMI.35 These those with HDP and AGA fetuses have
restricted fetal growth. findings challenge the mechanistic different hemodynamic dysfunctions

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ajog.org OBSTETRICS Original Research

performance should be considered when

different antihypertensive drugs are un-
Simplified schematic presentation of type-specific hemodynamics
der scrutiny to treat moderate to severe
forms of hypertension in pregnancy.39

Research implication
Differences in maternal cardiovascular
parameter matches other evidences
provided by uterine Doppler velocim-
etry,5 low vascular growth factors in
the first trimester,24 and placental
pathology.25 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 magnetic resonance
imaging.35 It also significantly outweighs
other determinants of hemodynamics in
pregnancy and should be studied as an
additional disease and not as a simply
A, nonpregnant state; B, normal pregnancy; C, hypertensive disorders of pregnancy (HDP) and demographic characteristic.
intrauterine growth restriction (IUGR); and D, HDP-appropriate for gestational age (AGA) or even large Both conditions focused on in our
for gestational age. In nonpregnant state, blood flow to uterine arteries is negligible; at mid- study represent a significant risk factor
pregnancy, it is 12% of whole cardiac output.37,38 Dimension of bellow represents dimension of left for cardiovascular disease (CVD) later in
ventricle beating at given rate, with certain stroke volume (SV) with each blow, at given heart rate life. Notably, in the presence of 3 or 4 risk
(HR), tube diameter, and curvature (smooth ¼ low total vascular resistance [TVR]; steep angle ¼ factors for metabolic syndrome,
high TVR) represent TVR; balloon content represents cardiac output (cardiac output ¼ SV  HR).
including obesity, the adjusted hazard
Blood pressure (BP) inside tubes is product of cardiac output and TVR (BP ¼ [f] cardiac output 
ratio for CVD later in life might increase
TVR). Blue vessels are veins and their dimension represents plasma volume relocated in capacitance
vessels and in splanchnic venous system. As compared to A, nonpregnant state, B, normal preg- by up to 10 times compared to unaf-
nancy induces increase in SV and cardiac output. These early adaptations are simultaneous with fected pregnancies.40 PE and SGA too are
major reduction of TVR that results in lower BP.47 In parallel, plasma volume increases by 1.2 L at 28 independent risk factors for CVD later in
weeks of gestation,49 with one fourth of it relocated in splanchnic venous system.21 Suboptimal life; the 2 risk factors together, PE with
plasma expansion in pregnancy was observed in pregnancies complicated by preeclampsia and fetal SGA, increase the risk of CVD as much
growth restriction.42 In C, HDP-IUGR, SV, HR, and cardiac output are lower than that in B, normal as 8-fold.41 However, the respective
pregnancy. TVR is much higher than in both A and B, resulting in higher BP values13-15,26 and pathophysiologies of these 2 different
plasma volume is lower than in normal pregnancies.38 In D, HDP-AGA, reported hemodynamic phenotypes of placental damage and
findings are controversial (see text for discussion). SV and cardiac output are similar or higher, and cardiovascular dysfunction appear to be
TVR similar or higher than in B, normal pregnancy. In reported cohorts, combination of 2 factors (TVR
totally different, and it is likely that
and cardiac output) results in higher BP. Under physiologic conditions, these fundamentally different
different preventive and therapeutic
states are influenced by many other variables, such as blood viscosity, anatomic and functional
vascular wall integrity, and ratio between lean and fat mass. strategies should be employed before,42
Ferrazzi et al. Maternal hemodynamics in hypertensive disorders of pregnancy. Am J Obstet Gynecol 2018.
during, and after pregnancy, as well as
later in life.43 These problems should be
investigated by future longitudinal
studies beginning with the early first
(Figure) and should be examined for spectrum of noninvasive technologies. trimester or even from the preconcep-
their cardiovascular performance when We believe that, beyond screening tion phase to the postpregnancy long-
maternal or fetal condition require in- tests, this diagnostic interrogation of term follow-up.
hospital monitoring and major antihy- maternal cardiovascular system should
pertensive treatment. As regards the be performed by cardiologists. PE obvi- Strengths and limitations
proper technique to adopt for these ex- ously remains a more serious disease The major limitation of this study is that
aminations, recent studies cover a wide than GH, yet maternal cardiovascular the only assessment of in utero growth

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was the birthweight percentile,44,45 and health care system. Am J Obstet Gynecol 18. Kubicek WG, Karnegis JN, Patterson RP,
we had no data on the longitudinal 2017;217:237-48.e16. Witsoe DA, Mattson RH. Development and
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Padoan A, Galan H. Blood flow volume of uterine formerly preeclamptic women and healthy par- Martino) and Department of Obstetrics and Gynecology,
arteries in human pregnancies determined using ous control subjects. Am J Obstet Gynecol Fondazione Istituto di Ricovero e Cura a Carattere Sci-
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tens Rep 2017;19:1-5. Stöhr EJ. Cardiac output and related ferrazzi@unimi.it

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Comparison of maternal demographics and clinical data between preeclampsia and gestational hypertension
appropriate-for-gestational-age groups
N 90 52
Maternal age, y 29 (26e32) 30 (26e33) .3
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
Thrombocyte count, 1000/mm 3
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.
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.

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