Download Effect of parity on maternal cardiac function during

Ultrasound Obstet Gynecol 2008; 32: 849–854
Published online 6 June 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5354
Effect of parity on maternal cardiac function during the first
trimester of pregnancy
O. M. TURAN, C. DE PACO, N. KAMETAS, A. KHAW and K. H. NICOLAIDES
Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK
K E Y W O R D S: cardiac output; echocardiography; parity; pregnancy
ABSTRACT
Objective To investigate maternal cardiac adaptation in
the first trimester of pregnancy with increasing maternal
parity.
Methods This was a cross-sectional study carried out at
the antenatal clinic of a teaching hospital. We examined
4689 pregnant women at 11 + 0 to 13 + 6 weeks of
gestation, performing two-dimensional echocardiography
of the maternal left ventricle. There were 2352 parous
and 2337 nulliparous women. The relationships between
parity, maternal cardiac function and neonatal birth
weight were analyzed.
Results Parous compared to nulliparous women had a
significantly higher median cardiac output (5.6 vs. 5.2
L/min) and median cardiac index (2.3 vs. 2.1 L/min/m2 ).
This was owing to a significantly higher median stroke
volume (73.5 vs. 70.5 mL), heart rate (76 vs. 75 bpm),
left ventricular outflow diameter (20.4 vs. 20.0 mm)
and lower total vascular resistance (1190.8 vs. 1253.7
dyne·s/cm5 ) and median uterine artery pulsatility index
(1.6 vs. 1.7). Mean arterial blood pressure was not
significantly different between the groups. There was
a progressive increase in all maternal cardiac variables, apart from total peripheral resistance, which
decreased with increasing parity. Birth weight was
higher in parous compared to nulliparous women
(3.39 vs. 3.23 kg) and it was independently related to
maternal hemodynamic variables and demographic and
social characteristics (age, height, weight, ethnicity,
smoking).
Conclusion Pregnancy in parous compared to nulliparous women is characterized by higher maternal cardiac
output and birth weight. Copyright  2008 ISUOG.
Published by John Wiley & Sons, Ltd.
INTRODUCTION
Maternal cardiovascular adaptation during pregnancy is
characterized by an initial drop in peripheral resistance
followed by intravascular space expansion and an increase
in cardiac output, due to an increase in both stroke volume
and heart rate. These changes reach their maximum level
at about mid-pregnancy, and are followed by a progressive
increase in peripheral resistance and a mild reduction in
systolic and diastolic function of the left ventricle (LV)
towards term1 – 9 .
Recently, more attention has been paid to the
interaction between maternal cardiovascular adaptation
and pregnancy complications. Pre-eclampsia and fetal
growth restriction have been shown to have distinct
patterns of maternal cardiac changes in pregnancy, with
worsening maternal cardiac function as the diseases
progress1 – 4 . There is a strong association between
parity and specific pregnancy complications. Nulliparous
women have a higher incidence of pre-eclampsia5,6 , while
multiparity is considered a risk factor for peripartum
cardiomyopathy7,8 and cardiovascular disease in later
life, even after controlling for other medical, demographic
or socioeconomic risk factors9,10 .
In view of the differences in pregnancy outcome
between parous and nulliparous women we aimed to
compare maternal LV cardiac function in uncomplicated
pregnancies with increasing parity.
METHODS
This was a cross-sectional study of maternal cardiac
function in women attending for routine antenatal care
in a London teaching hospital at 11 + 0 to 13 + 6 weeks’
gestation. This study is part of an ongoing study on
maternal cardiovascular adaptation in pre-eclampsia and
growth restriction. During 4 years (June 2003 to July
Correspondence to: Dr N. Kametas, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill, London
SE5 9RS, UK (e-mail: [email protected])
Accepted: 8 February 2008
Copyright  2008 ISUOG. Published by John Wiley & Sons, Ltd.
ORIGINAL PAPER
Turan et al.
850
2007) 5599 women attending for routine first-trimester
screening were invited to participate in the study, which
was approved by the Research Ethics Committee of King’s
College Hospital, London, UK. Written informed consent
was obtained from the patients. The inclusion criteria
were singleton pregnancy, no previous adverse medical
history or medication and normal blood pressure (systolic
< 140 mmHg and diastolic < 90 mmHg). Pregnancies
with adverse outcome such as miscarriage, in-utero death,
preterm delivery before 37 weeks’ gestation, hypertensive
disorders of pregnancy and those with birth weight less
than the 10th percentile for gestation were excluded from
the study. Thus, a total of 910 women were excluded and
therefore the final study population consisted of 4689
women, 2352 parous and 2337 nulliparous.
Gestational age was calculated from the last menstrual
period and was confirmed by ultrasound biometry
in the first trimester. Pre-eclampsia and pregnancyinduced hypertension (PIH) were defined according to
the guidelines of the International Society for the Study
of Hypertension in Pregnancy11 . The diagnosis of PIH
requires two recordings of diastolic blood pressure of
> 90 mmHg at least 4 h apart in previously normotensive
women, while the diagnosis of pre-eclampsia requires two
recordings of diastolic blood pressure of > 90 mmHg at
least 4 h apart plus proteinuria of 300 mg or more in
24 h, or two readings of at least 2+ on dipstick analysis
of midstream or catheter urine specimens if no 24 h
collection is available.
Blood pressure measurements were performed according to the recommendations of the British Hypertension
Society12 , and mean arterial pressure (MAP) was calculated from the equation:
MAP = (systolic pressure + [2 × diastolic pressure])/3.
The cardiac study of the patients was performed after a
rest period of 15 min in the left lateral decubitus position.
Two-dimensional (2D) echocardiography was performed
using a 3.5-MHz transducer (Toshiba Aplio, Toshiba
Corporation, Tokyo, Japan) according to the guidelines
of the American Society of Echocardiography13 . Stroke
volume was computed as the product of the crosssectional area of the left ventricular (LV) outflow
tract and the velocity time integral of the pulsed
Doppler subaortic waveform measured in the fivechamber view. Cardiac output was calculated as the
product of heart rate and stroke volume14 . In order to
normalize maternal cardiac output for body size, the
measurements were divided by the patient’s height to
the power of 1.8315,16 . Echocardiography was performed
by obstetricians who had been trained by cardiologists.
Each operator performed about 150 scans during his/her
training period, until interobserver and intraobserver
variability, as assessed by the coefficient of variation
between measurements, fell below 2.5 and 1.5% for
the LV outflow tract and aortic velocity time integral,
respectively. Each variable was calculated as the average
of two measurements on two different cardiac cycles.
Copyright  2008 ISUOG. Published by John Wiley & Sons, Ltd.
Transabdominal ultrasound examination was carried
out for the measurement of uterine artery pulsatility index
(PI) as previously described17 . In brief, a sagittal section of
the uterus was obtained and the cervical canal and internal
cervical os were identified. Subsequently, the transducer
was gently tilted from side to side and color flow mapping
was used to identify each uterine artery along the side
of the cervix and uterus at the level of the internal os.
Pulsed-wave Doppler was used with the sampling gate set
at 2 mm to cover the whole vessel, and care was taken
to ensure that the angle of insonation was less than 50◦ .
When three similar consecutive waveforms were obtained
the PI was measured and the mean PI of the left and right
arteries was calculated.
The ultrasound findings and patient characteristics,
including demographic data and obstetric and medical
history, were entered into a computer database. Data
on pregnancy outcome were collected from the hospital
maternity records or their general medical practitioners.
The obstetric records of all patients with pregnancyassociated hypertension were examined to confirm the
diagnosis.
Statistical analysis
The Kolmogorov–Smirnov test was used to assess normality of the distribution of the data and the Mann–Whitney
or Chi-square test, as appropriate, was performed in order
to examine the differences in the demographic or cardiac
characteristics between the examined populations.
For each cardiac variable, the independent contribution of maternal demographic characteristics, gestational
age on the study day, parity and uterine artery PI was
investigated by multiple regression analysis. The independent variables were: maternal age; weight; height;
ethnicity (1 = White, 2 = Black, 3 = Asian and Oriental,
4 = Mixed); smoking (yes or no); gestational age in days;
and parity. Similarly, the independent contribution of the
abovementioned variables, cardiac output and MAP in the
prediction of birth weight was investigated by multiple
regression analysis.
In order to assess whether the differences between
parous and nulliparous women were progressively
increasing with increasing parity, the population was
divided further into three groups: the first one comprised
nulliparous women, the second women with parity 1 and
the third women with parity ≥ 2. In order to assess the progressive increase of the cardiac variables with increasing
parity, Cuzick’s test for trend was used and pairwise comparisons were performed with the Kruskal–Wallis test.
The statistical packages SPSS 12.0 (SPSS for Windows,
SPSS Inc., Chicago, IL, USA) and StatsDirect (StatsDirect
statistical software, StatsDirect Ltd, England: 2002) were
used.
RESULTS
The demographic characteristics of nulliparous and
parous women are shown in Table 1. There were
Ultrasound Obstet Gynecol 2008; 32: 849–854.
Maternal parity and cardiac function in the first trimester
significant differences between parous and nulliparous
women’s cardiac variables, peripheral resistance and
mean uterine artery PI but not in MAP (Table 2). The
results of the multiple regression analysis examining
the independent contribution of maternal demographic
characteristics and parity to the cardiac variables and the
independent contribution of maternal demographic and
cardiac parameters in the prediction of birth weight are
presented in Table 3. When adjusted for maternal and
gestational age, weight, height, smoking and ethnicity,
parity was an independent predictor for cardiac output,
cardiac output index, stroke volume, LV outflow tract
diameter (LVOTD), total peripheral resistance (TPR)
and heart rate. On the other hand, parity was not
an independent predictor for MAP, LV velocity time
integral (LVVTI) and uterine artery PI. When adjusted
for maternal somatometric characteristics and cardiac
variables maternal height, weight, ethnicity, cardiac
output, MAP and parity were independent predictors
for birth weight.
With increasing parity there was a progressive increase
in cardiac output (Cuzick’s trend test P < 0.0001), cardiac output index (Cuzick’s trend test P < 0.0001), stroke
volume (Cuzick’s trend test P < 0.0001), LVOTD (Cuzick’s trend test P < 0.0001), LVVTI (Cuzick’s trend test
P = 0.01), heart rate (Cuzick’s trend test P < 0.0001)
and a decrease in TPR (Cuzick’s trend test P < 0.0001)
(Figure 1).
851
DISCUSSION
The results of this study have demonstrated that,
after adjusting for maternal somatometric characteristics,
maternal left ventricular systolic function during the first
trimester of pregnancy in parous compared to nulliparous
women is characterized by a higher cardiac output and
cardiac index mainly owing to a higher heart stroke
volume, which in turn was due to an increase in LVOTD
rather than an increase in blood flow velocity. MAP
and peripheral resistance were lower in parous women.
The differences between parous and nulliparous women
progressively increased with parity. Birth weight was
higher in parous compared to nulliparous women and
it was independently related to maternal demographic
characteristics (age, height, weight, ethnicity, parity)
and maternal hemodynamic parameters (cardiac output,
MAP, uterine artery PI).
In our data, parous compared to nulliparous women
were older and had a higher prevalence of black
women and a lower prevalence of white women. Age,
height and race are important determinants of cardiac
structure and function. Hinderliter et al. have shown
that LV wall thickness and TPR are higher, while
resting cardiac output is lower, in healthy, adult black
compared to white women18 . In non-pregnant subjects
LVOTD has been shown to be related to the subject’s
height19 , and age is related to cardiac output. In order,
therefore, to account for these disparities between the
Table 1 Demographic characteristics of the examined populations
Parameter
Parous (n = 2352)
Nulliparous (n = 2337)
Age (years, median (interquartile range))
Gestational age at examination (days, median (range))
Height (m, median (interquartile range))
Weight (kg, median (interquartile range))
Ethnicity (%)
White
Black
Asian-Oriental
Mixed
Smoker (%)
Birth weight (kg, median (interquartile range))
Gestational age at delivery (days, median (interquartile range))
33.7 (29.7–36.9)
88.0 (85–90)
1.63 (1.60–1.65)
66.0 (59.6–74.0)
30.6 (26.4–34.2)*
88.0 (86–90)*
1.63 (1.59–1.68)
64.0 (58.0–71.0)*
68.7
22.4
5.4
3.3
7.4
3.54 (3.26–4.14)
279.0 (272.0–285.0)
71.9*
17.6*
6.5
3.8
5.8*
3.43 (3.17–3.73)*
281.0 (274.0–287.0)*
*Statistically significant difference between parous and nulliparous populations.
Table 2 Maternal cardiac parameters in parous and nulliparous women (median (interquartile range))
Parameter
Cardiac output (L/min)
Cardiac index (L/min/m2 )
Stroke volume (mL)
Left ventricular outflow tract diameter (mm)
Left ventricular velocity time integral
Heart rate (bpm)
Mean arterial pressure (mmHg)
Total vascular resistance (dyne·s/cm5 )
Mean uterine artery pulsatility index
Parous (n = 2352)
Nulliparous (n = 2337)
P
5.6 (4.9–6.3)
2.3 (1.9–2.6)
73.5 (65.1–82.6)
20.4 (19.4–21.3)
22.6 (20.5–25.0)
76.0 (70.0–83.0)
83.3 (78.0–88.5)
1190.8 (1049.9–1353.2)
1.6 (1.3–1.9)
5.2 (4.6–6.0)
2.1 (1.9–2.2)
70.5 (62.2–79.6)
20.0 (19.1–21.0)
22.5 (20.2–24.5)
75.0 (69.0–82.0)
83.3 (77.6–88.3)
1253.7 (1105.7–1430.8)
1.7 (1.4–2.0)
< 0.0001
< 0.0001
< 0.0001
< 0.0001
0.01
0.003
NS
< 0.0001
0.003
NS, not significant.
Copyright  2008 ISUOG. Published by John Wiley & Sons, Ltd.
Ultrasound Obstet Gynecol 2008; 32: 849–854.
Turan et al.
852
Table 3 Multiple regression analysis of cardiac parameters and birth weight
Parameter
Regression equation
Cardiac output (CO)
CO = 1.6 + (0.2 × Parity) + (0.03 × Wt) + (0.3 × Smoker) − (0.3 × Black) −
(0.2 × Asian) + (0.03 × MAP)
COI = 4.4 + (0.09 × Parity) + (0.01 × Wt) − (0.02 × Ht) + (0.1 × Smoker) −
(0.1 × Black) + (0.01 × MAP)
SV = 7.8 + (1.9 × Parity) + (0.3 × Wt) + (0.2 × Ht) + (2.9 × Smoker) + (0.05 ×
MAP) + (0.1 × Age) − (5.9 × Black) − (4.9 × Asian) − (2.1 × Mixed)
HR = 68.3 + (1.2 × Parity) + (0.04 × Wt) + (0.3 × MAP) − (0.2 × Ht) − (0.2 ×
Age) + (0.2 × GA) + (1.9 × Black) + (2.3 × Asian)
LVOTD = 11.7 + (0.3 × Parity) + (0.03 × Wt) + (0.04 × Ht) − (0.01 × Age) −
(0.6 × Black) − (0.5 × Asian)
LVVTI = 22.7 + (0.03 × Wt) − (0.02 × Ht) + (0.06 × Age) + (0.6 × Smoker) −
(0.6 × Black) − (0.6 × Asian)
MAP = 90.7 + (0.2 × Wt) − (0.1 × Ht) + (0.1 × Age) − (1.5 × Smoker) − (1.1 ×
Parity) − (0.1 × GA) − (0.6 × Black) − (1.1 × Asian) − (2.177 × Mixed) +
(1.5 × CO)
TPR = 1992.6 − (3.4 × Wt) − (1.8 × Ht) + (1.9 × Age) − (58.8 × Smoker)
− (61.1 × Parity) − (2.99 × GA) + (1.9 × Age) + (46.5 × Asian) + (59.6 ×
Black)
PI = 3.541 − (0.003 × Ht) − (0.004 × Age) − (0.01 × GA) + (0.06 × Black) −
(0.042 × CO)
BW = 1294.3 + (84.6 × Parity) + (12.2 × Ht) + (5.4 × Wt) − (113.9 × Black) +
(29.2 × CO) − (2.5 × MAP) − (69.3 × PI)
Cardiac output index (COI)
Stroke volume (SV)
Heart rate (HR)
LV outflow tract diameter (LVOTD)
LV velocity time integral (LVVTI)
Mean arterial pressure (MAP)
Total peripheral resistance (TPR)
Uterine artery pulsatility index (PI)
Birth weight (BW)
R2
P
0.20
< 0.0001
0.20
< 0.0001
0.19
< 0.0001
0.10
< 0.0001
0.19
< 0.0001
0.30
< 0.0001
0.18
< 0.0001
0.08
< 0.0001
0.03
< 0.0001
0.11
< 0.0001
Ethnicity was rated on the following scale: 1, White; 2, Black; 3, Asian and Oriental; 4, Mixed. Smoking was rated 1 (yes) or 0 (no). GA,
gestational age (days); Ht, height (m); Wt, weight (kg).
demographic characteristics of the examined groups,
we controlled for them in multiple regression models.
Our multiple regression analyses confirmed the abovementioned observations, since Afro-Caribbean ethnicity
was associated with lower cardiac output and higher
peripheral resistance, and height was an independent
predictor of stroke volume and cardiac output.
There are few and conflicting data in the literature
about parity and maternal cardiac function. Our findings
are in agreement with those of Hart et al.20 , who
found in seven nulliparous and 12 parous women a
higher resting heart rate, larger LVOTD and higher
aortic compliance in parous compared to nulliparous
women. Our data also agree with those of Clapp and
Capeless21 , who examined serially during pregnancy and
postpartum 15 nulliparous and 15 parous women and
showed a similar trend of cardiovascular changes during
pregnancy for both groups, but higher stroke volume and
cardiac output and lower TPR in the parous compared
to the nulliparous women; similarly, they also did not
demonstrate any difference between the two groups in
MAP. However, in this study M-mode echocardiography
was used to assess cardiac function, and this modality
has not been validated in pregnancy. On the other
hand, 2D Doppler echocardiography, which was used
in our study, has been shown to correlate well during
pregnancy with ‘gold standard’ invasive techniques for the
measurement of cardiac output14,22 . Contrary to Clapp
and Capeless, van Oppen et al.23 reported lower stroke
volume, heart rate and MAP in 27 parous compared to
23 nulliparous women. Methodological issues, however,
make the interpretation of the results of this study
problematic. Measurement of maternal cardiac output
Copyright  2008 ISUOG. Published by John Wiley & Sons, Ltd.
was performed by the thoracic electrical bioimpedance
technique that has been criticized for its applicability
in pregnancy24 . Furthermore, the fact that 75% of the
initially recruited population was excluded from the
study either because of incomplete series of measurements
(15%) or because of pregnancy complications (60%)
raises methodological concerns, as it makes it difficult
to be certain as to whether the study had the appropriate
power and whether the recruited patients were truly
representative of the general low-risk pregnant women
of their local population.
The differences in cardiac function between nulliparous
and parous women could represent a faster response to the
early pregnancy stimuli that lead to the maternal reduction
in peripheral resistance and increase in cardiac output. It
could be that their previous pregnancy mobilized adaptational mechanisms that on a subsequent pregnancy are
more rapidly deployed. However, the higher cardiac output in these women could also represent an exaggerated
response rather than simply an earlier one that finally
reached equal magnitude during the first trimester.
The differences between parous and nulliparous women
could be the result of a remodeling of the heart from
previous pregnancies. One could use the heart changes of
endurance athletes as a model of physiological myocardial
hypertrophy to compare with the changes in the hearts
of pregnant women. Both in endurance athletes25 and
in pregnant women2,26 – 28 increases of 45% have been
reported in LV mass. However, cardiac changes in athletes
regress rapidly after the cessation of training activity, with
LV wall thickness decreasing exponentially after inactivity
with a half-time of about 5 days29 . In normal pregnancy
this regression takes longer, with LVOTD, stroke volume
Ultrasound Obstet Gynecol 2008; 32: 849–854.
Maternal parity and cardiac function in the first trimester
(a) 10.0
853
(b) 2000
Total peripheral resistance (dyne.s/cm5)
Cardiac output (L/min)
8.0
6.0
1500
1000
4.0
2.0
500
Nulliparous
n = 2337
Parity 1
n = 1563
Parity > 1
n = 789
Nulliparous
n = 2337
Parity 1
n = 1563
Parity > 1
n = 789
Figure 1 Cardiac output (a) and total peripheral resistance (b) in nulliparous and parous women (parity 1 and more than 1) at 11 + 0 to
13 + 6 weeks’ gestation. White lines and boxes represent median and interquartile range and whiskers represent extreme values.
and cardiac output remaining above and TPR below
pre-pregnancy levels for at least 6 months30 and up to
1 year post delivery21 . Similarly, LV mass remains above
prepregnancy levels for at least 6 months post delivery30 .
It may even take decades before these changes return to
their initial values31 .
Animal studies have shown that the aortic diameter
increases as a result of acute volume expansion32 .
Therefore, the increase in LVOTD could simply represent
a better response of a more compliant aorta to a larger
blood volume20 . Whether there is a degree of a residual
increase in the LVOTD from the previous pregnancy, as
a result of material property changes in the aortic wall,
remains to be investigated.
The higher cardiac output and lower peripheral resistance in parous compared to nulliparous women could
be due to the fact that parous healthy women without previous pregnancy hypertensive disease represent
a ‘screened’ population, with reduced risk of cardiovascular impairment. There is an increasing amount of
evidence that pregnancy is a screening period for the risk
of cardiovascular complications9 . The fact that women
with hypertensive disorders in pregnancy have a higher
Copyright  2008 ISUOG. Published by John Wiley & Sons, Ltd.
risk of cardiovascular disease in later life9 is suggestive
that pregnancy unmasks women with vulnerability in
their cardiovascular homeostasis but, on the other hand,
it may confer a reduced risk for women who have uncomplicated pregnancies. One cannot, however, completely
exclude the possibility of pregnancy itself posing risks
to the maternal cardiovascular function, since data by
Ness et al.10 , reviewing studies examining the relationship
between gravidity/parity and the risk for cardiovascular
disease in women, are suggestive of a 30–70% increase
in the risk of coronary artery disease in women with high
parity, even after controlling for age, socio-economic status, education, cigarette smoking, hypertension, glucose
intolerance and cholesterol levels. In support of the above,
parity has been shown to be an independent risk factor for
peripartum cardiomyopathy7,8 . Veille, in his review, has
shown that in the reported cases of peripartum cardiomyopathy in the literature about 85% of cases occurred in
parous women8 .
In this study we compared cardiac function in
parous and nulliparous women only in the first
trimester of pregnancy. The evolution of differences with
gestation remains to be investigated. In our data, birth
Ultrasound Obstet Gynecol 2008; 32: 849–854.
Turan et al.
854
weight was higher in parous compared to nulliparous
women. Furthermore, maternal parity and cardiac output
remained independent contributors in predicting birth
weight even after controlling for maternal demographic
characteristics. The effect of maternal parity on birth
weight has been previously described33 – 35 . However, the
additional independent contribution of maternal central
(cardiac output) and peripheral (MAP, uterine artery PI)
hemodynamic characteristics in determining birth weight
is of interest and warrants further investigation.
16.
17.
18.
ACKNOWLEDGMENT
This study was funded by The Fetal Medicine Foundation
(registered charity 1037116).
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