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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. 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