OBJECTIVE: To investigate maternal cardiac output in the first trimester as a predictor of preeclampsia and delivery of small for gestational age (SGA) infants.
METHODS: In women attending for routine care between 11+0 and 13+6 weeks of gestation, we recorded maternal variables and measured cardiac output by echocardiography. We compared cardiac output in those that developed preeclampsia (n=83), pregnancy-induced hypertension (PIH) (n=87), or SGA (n=532) with those unaffected by preeclampsia, PIH, or SGA (n=3,591). Regression analysis was used to first determine which of the factors among the maternal variables were significant predictors of cardiac output in the unaffected group and, secondly, to predict each complication by a combination of maternal variables and cardiac output.
RESULTS: In the unaffected group, cardiac output increased with gestation and maternal weight and decreased with maternal age. Cardiac output was higher in parous women, in cigarette smokers, in those taking antihypertensive or β-mimetic medications, and in those conceiving after in vitro fertilization, and lower in women of Afro-Caribbean origin. Compared with the unaffected group, cardiac output was significantly higher in the preeclampsia and PIH groups and lower in the SGA group. In screening by cardiac output and maternal variables, for a 10% false-positive rate, the detection rates were 43.4% for all preeclampsia, 52% for preeclampsia without SGA, 23.3% for PIH, and 23.9% for SGA.
CONCLUSION: In pregnancies complicated by preeclampsia, PIH, and SGA, alterations in maternal cardiac output predate the clinical onset of the disorders by several months. Maternal cardiac output in the first trimester is increased in women who develop preeclampsia and decreased in women who deliver SGA infants.
LEVEL OF EVIDENCE: II
Maternal cardiac output in the first trimester is increased in women who develop preeclampsia and decreased in women who deliver small for gestational age infants.
From the Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, United Kingdom.
Supported by a grant from the Fetal Medicine Foundation (Charity No. 1037116).
Corresponding author: Prof. K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, Denmark Hill, London SE5 8RX; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
Blood pressure is the product of cardiac output and peripheral resistance. In patients with essential hypertension cardiac output is increased but peripheral resistance is either increased if their weight is normal or decreased if they are obese.1 These differences in hemodynamic profile may be due to the degree of associated insulin resistance-related hyperinsulinemia.2 Consequently, hypertension, like diabetes, can be subdivided into two types that differ in pathophysiology and preferred treatment.3 The first type, found more frequently in black hypertensives, is characterized by low plasma renin levels and hypervolemia and responds better to calcium channel blockers and diuretics. The second type is characterized by high renin levels and vasoconstriction and responds better to angiotensin-converting enzyme inhibitors and β-blockers.4
In pregnancy, preeclampsia has been considered for a long time a disease associated with increased peripheral resistance and reduced cardiac output.5 However, the use of two-dimensional echocardiography has made it possible to perform longitudinal studies in pregnancy and demonstrate that the preclinical phase of preeclampsia is characterized by a hyperdynamic high-output-low-resistance state which changes during the disease to a low-output-high-resistance state.6–8
There is emerging evidence that preeclampsia is a heterogeneous disorder with variable effects on fetal growth. In general, early-onset disease is associated with the birth of small for gestational age (SGA) babies, whereas in late-onset disease, fetal growth is normal or increased.9–11 Additionally, in preeclampsia the prevalence of placental lesions due to impaired trophoblastic invasion of the maternal spiral arteries and Doppler evidence of increased impedance to flow in the uterine arteries are inversely related to the gestational age at delivery.12–14
In this prospective first-trimester screening study, we investigate the performance of maternal cardiac output in predicting preeclampsia with and without SGA.
MATERIALS AND METHODS
This is was a prospective screening study for preeclampsia and SGA in singleton pregnancies between March and November 2006. All patients were attending our center for routine assessment of risk for chromosomal abnormalities by measurement of fetal nuchal translucency thickness and maternal serum-free β-hCG and pregnancy-associated plasma protein A at 11+0 to 13+6 weeks of gestation.15,16 The inclusion criteria were singleton pregnancy with a live fetus identified at the 11+0 to 13+6 weeks scan. Written informed consent was obtained from the women agreeing to participate in the study, which was approved by King's College Hospital Ethics Committee.
Patients were asked to complete a questionnaire on maternal age, ethnic origin (Caucasian, Afro-Caribbean, Indian or Pakistani or Bangladeshi, Chinese or Japanese, and Mixed), cigarette smoking during pregnancy (yes or no), alcohol intake during pregnancy (yes or no), drug abuse during pregnancy (yes or no), medical history (including chronic hypertension, diabetes mellitus, antiphospholipid syndrome, thrombophilia, human immunodeficiency virus [HIV] infection, and sickle cell disease), medication (including antihypertensive, antidepressant, antiepileptic, antiinflammatory, antiretroviral, antithyroid, aspirin, betamimetic, insulin, lithium, steroids, thyroxine), parity (nulliparous if no delivery beyond 23 weeks or parous), obstetric history (including previous pregnancy with preeclampsia), and family history of preeclampsia (sister, mother, or both). The maternal weight and height were measured, and the body mass index (BMI) was calculated in kilograms per meter2. Transabdominal ultrasound examination was carried out for measurement of fetal crown-rump length and nuchal translucency thickness for diagnosis of any major fetal defects.
The maternal cardiac output was assessed with each woman positioned in the left lateral decubitus position with her left arm behind her head. Two dimensional echocardiography was performed according to the guidelines of the American Society of Echocardiography.17 A 3.5-MHz ultrasound transducer (Toshiba Aplio CV, Toshiba Corporation, Tokyo, Japan, or Voluson 730 Expert, GE Medical systems, Milwaukee, WI) was positioned in the fourth intercostal space, just to the left of the sternum to visualize the long axis view of the heart. The left ventricular outflow tract diameter was measured 1 cm from the aortic valve, and its cross-sectional area was calculated. Two measurements were made and the average recorded. The transducer was subsequently placed in the cardiac apex and tilted toward the chest to visualize the five-chamber view of the heart. Pulsed wave Doppler was used with the sample volume placed about 5 mm proximal to the aortic valve. Care was taken to ensure that the angle of insonation was less than 20°. When three similar consecutive waveforms were obtained, the velocity time integral was measured in each waveform and the average measurement was recorded. Stroke volume was computed as the product of the cross-sectional area of the aorta and the velocity time integral, and cardiac output was calculated as the product of stroke volume and heart rate. To normalize maternal cardiac output for body size, the measurements were indexed by the patient's height1.83.1,18 The results of cardiac output were not given to the women or their doctors and did not influence the subsequent management of the pregnancies.
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 pregnancy-associated hypertension were examined to determine if the condition was preeclampsia or pregnancy-induced hypertension (PIH). Similarly, for quality control we examined the records of 500 randomly selected cases without pregnancy-associated hypertension.
The patients were subdivided into four groups: preeclampsia, PIH, SGA, and unaffected by any of the previous three. In preeclampsia and PIH, we included all cases with SGA, but in the SGA group we excluded cases with preeclampsia and PIH.
The definitions of preeclampsia and PIH were according to the guidelines of the International Society for the Study of Hypertension in Pregnancy.19 In preeclampsia the diastolic blood pressure should be more than 90 mm Hg on at least two occasions 4 hours apart in previously normotensive women and proteinuria of 300 mg or more in 24 hours or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-hour collection is available. In PIH the diastolic blood pressure should be more than 90 mm Hg on at least two occasions 4 hours apart in previously normotensive women in the absence of significant proteinuria.
In all patients the birth weight was converted into a percentile after correction for gestation at delivery and sex of the newborn, maternal ethnic origin, weight, height, and parity (Gardosi J, Francis A. Software program for the calculation of customized birth weight percentiles. Version 6.2, 2000–2007. Published on http://www.gestation.net). The newborn was considered to be SGA if the birth weight was less than the 10th percentile.
The analysis of variance test (with the Bonferroni post hoc test) and the χ2 test were used to compare the demographic characteristics of the unaffected group with each group with pregnancy complications. The distribution of cardiac output was made Gaussian after logarithmic transformation, and the normality of the distribution was confirmed by the Kolmogorov-Smirnov test. Multiple regression analysis was used to determine which of the factors among the maternal characteristics, medical and obstetric history, and gestation are significant predictors of log cardiac output in the unaffected group. All factors shown in Table 1 were included and backward stepwise analysis was used so that the final model included only significant predictors. The distribution of log cardiac output, expressed as multiples of the median (MoM) of the unaffected group, were determined in the total preeclampsia, preeclampsia without SGA, preeclampsia with SGA, PIH, and SGA groups. Box and whisker plots were constructed, and the t test was used to determine the significance of differences in mean log MoM cardiac output between the unaffected group and each of the other groups. Multiple regression analysis was then used to determine the factors, including log MoM cardiac output, that have a significant contribution in predicting total preeclampsia, preeclampsia without SGA, preeclampsia with SGA, PIH, and SGA. Performance of screening was described by the receiver operating characteristics curve.
Maternal cardiac output was successfully measured in all 4,617 consecutive singleton pregnancies with a live fetus identified at the 11+0 to 13+6 weeks scan. We excluded 324 (7.0%) because they had missing outcome data (n=250), the pregnancies resulted in fetal death or miscarriage before 24 weeks of gestation (n=40), the pregnancies were terminated for fetal abnormalities (n=23) or social reasons (n=6), or the newborns had major defects (n=5). In the remaining 4,293 cases, there were 83 (1.9%) that developed preeclampsia, 87 (2.0%) that developed PIH, 532 (12.4%) that did not develop preeclampsia or PIH but delivered SGA newborns, and 3,591 (83.6%) cases that were unaffected by preeclampsia, PIH, or SGA. In the quality control assessment of the 500 with reported normal outcome, there was one case of PIH. The characteristics of the outcome groups are summarized in Table 1. There were no significant differences in demographic and pregnancy characteristics between those included and those excluded from the analysis.
In the multiple regression model for log cardiac output, significant independent contributions were provided by maternal ethnic origin, age, weight, multiparity, smoking, antihypertensive and betamimetic medication, method of conception, and fetal crown-rump length but not medical condition, alcohol intake, drug abuse, or family history of preeclampsia (Table 2).
In each patient we 1) log-transformed the measured cardiac output (log-observed cardiac output), then 2) used the formula that follows for log cardiac output in the unaffected group to calculate the log-expected cardiac output, and 3) calculated the ratio of the observed to expected values:
log (observed/expected)=log MoM cardiac output= log observed-log expected.
The mean log MoM cardiac output was 0.000 (95% confidence interval [CI] –0.0025 to 0.0025) in the unaffected group, 0.0261 (95% CI 0.0065 to 0.0457) in the preeclampsia group, 0.0257 (95% CI 0.0079 to 0.0435) in the PIH group, and –0.0085 (95% CI –0.0157 to –0.0013) MoM in the SGA group (Fig. 1). In the preeclampsia group, log MoM cardiac output increased significantly with birth weight percentile (r=0.346, P<.001; Fig. 2), and the mean value was 0.0382 (95% CI 0.0108 to 0.0656) in the preeclampsia group without SGA and 0.0111 (95% CI –0.0174 to 0.0396) in the preeclampsia group with SGA. Compared with the unaffected population, the mean log MoM cardiac output was higher in preeclampsia (t test –2.62, P=.01), preeclampsia without SGA (t test –2.79, P=.008), and in PIH (t test –3.02, P=.003), lower in SGA (t test 2.3, P=.03), and not significantly different in preeclampsia with SGA (t test –0.78, P=.44).
Multiple regression analysis demonstrated that log MoM cardiac output provided significant contribution in the prediction of all conditions in which log MoM cardiac output was significantly different from the unaffected group. Significant independent contributions for all preeclampsia and preeclampsia without SGA were provided by log cardiac output, maternal ethnic origin, personal or family history of preeclampsia, and weight (Table 3; all preeclampsia, R2=0.162, P<.001; preeclampsia without SGA, R2=0.159, P<.001.)
Significant prediction for PIH was provided by log MoM cardiac output (odds ratio [OR] 67.0, 95% CI 4.3 to 1,034.3) and family (mother) history of preeclampsia (OR 3.1, 95% CI 1.6 to 6.2), but only a small amount of the variability in results was explained by the model (R2=0.024). Similarly, significant prediction for SGA was provided by log MoM cardiac output (OR 0.29, 95% CI 0.09 to 0.92), smoking (OR 3.1, 95% CI 2.4 to 4.1), betamimetic medication (OR 2.9, 95% CI 1.7 to 5.4), crown-rump length (OR 0.97, 95% CI 0.96 to 0.99), and ethnic origin (Afro-Caribbean, OR 1.4, 95% CI 1.1 to 1.8; Indian, Pakistani, or Bangladeshi, OR 1.5, 95% CI 1.0 to 2.2; Mixed, OR 1.6, 95% CI 1.0 to 2.5) with R2 of 0.049.
The area under the receiver operating characteristics curve was 0.813 (0.770 to 0.856) for all preeclampsia, 0.830 (0.773 to 0.887) for preeclampsia without SGA, 0.630 (0.568 to 0.692) for PIH, and 0.629 (0.602 to 0.655) for SGA (Fig. 3). For a 10% false-positive rate, the detection rates were 43.4% (32.5–54.7%) for all preeclampsia, 52.2% (36.9–67.1%) for preeclampsia without SGA, 23.3% (14.8–33.6%) for PIH, and 23.9% (20.3–27.7%) for SGA.
In this screening study for preeclampsia and SGA, we measured maternal cardiac output in a large population of women attending for routine care in early pregnancy. We chose 11+0 to 13+6 weeks as the gestation for screening because this is emerging as the first hospital visit of pregnant women at which combined sonographic and biochemical testing for fetal defects and pregnancy complications is carried out.16,20
In the unaffected group, which did not develop hypertensive disorders or SGA, maternal cardiac output increased with gestation and maternal weight and decreased with maternal age. It was higher in parous women, in cigarette smokers, those taking antihypertensive or betamimetic medications, and in those conceiving after in vitro fertilization and was lower in women of Afro-Caribbean origin.
These findings are compatible with the results of previous studies. In normal pregnancy cardiac output increases from as early as 5 weeks of gestation.21 The higher cardiac output observed in pregnancies conceived after in vitro fertilization may be the consequence of the expanded intravascular volume due to human chorionic gonadotropin or luteinizing hormone administration for oocyte maturation, which causes a drop in peripheral resistance and an increase in cardiac output.22 The observed racial differences have also been reported in nonpregnant individuals with lower resting cardiac output in black than white women.23 Similarly, cardiac output has been shown to decrease with advancing age.24 Cigarette smoking increases sympathetic activity and causes acutely an increase in both stroke volume and heart rate.25 Two previous studies on a combined total of 49 patients reported that, in parous compared with nulliparous women, cardiac output was higher.26,27
Obesity is a known risk factor for hypertension and preeclampsia.27 In healthy nonpregnant individuals, the left ventricular mass and cardiac output increase with BMI due to an increase in stroke volume.1,28–30 The increased cardiac output in obese individuals is primarily aimed at meeting the increased metabolic demands of the fat-free mass rather than those of the adipose tissue.31
Cardiac output was increased in women taking antihypertensive and betamimetic drugs. Essential hypertension is associated with a hyperdynamic circulation, and the increase in cardiac output resembles that seen in obese subjects.29 However, the obesity-related increase in cardiac output is associated with reduced peripheral resistance and normal catecholamine levels whereas that associated with chronic hypertension is characterized by increased peripheral resistance and high catecholamine levels.32 The association between betamimetic drugs and increased cardiac output is due to both an increase in stroke volume and a vasodilatory effect resulting in a compensatory tachycardia. The administration of betamimetics causes a 40–60% increase in cardiac output in both nonpregnant individuals and in pregnant women during tocolysis.33–35
The risk of developing preeclampsia is associated with maternal ethnic origin, age, BMI, and family or personal history of preeclampsia. These findings are compatible with the results of previous studies.36 Similarly, the risk for SGA is associated with maternal ethnic origin, smoking, and the use of betamimetics. The use of betamimetics in our population was for treatment of asthma, and our finding is in agreement with studies that reported an increased prevalence of SGA in asthmatic patients, especially in those with persistent and daily symptoms during pregnancy.37–39 As far as smoking is concerned, previous studies have shown a reduction in birth weight in smokers of up to 450 g40 and a doubling of the prevalence of low birth weight infants in smoking compared with nonsmoking mothers.41
Maternal cardiac output at 11+0 to 13+6 weeks in women destined to develop preeclampsia was increased. These results provide further support to the hypothesis that the preclinical phase of preeclampsia is characterized by a hyperdynamic high cardiac output state.5–7 Easterling et al6 carried out a longitudinal study in 98 nulliparous pregnant women and showed that, in the nine who developed preeclampsia, cardiac output was increased throughout their pregnancy. Similarly, Bosio et al7 examined longitudinally 400 women and confirmed that, in the 20 women who developed preeclampsia and in the 24 women who developed PIH, the circulation was hyperdynamic during the preclinical phase of the disease, but during the clinical phase of preeclampsia there was a marked reduction in cardiac output and increase in peripheral resistance. In these two studies, all cases with preeclampsia delivered after 36 weeks, and therefore the disease is likely to have been of the late-onset type that is not usually associated with SGA.6,7 We found that, in the preeclampsia group, cardiac output increased with birth weight percentile, and consequently in preeclampsia with SGA fetuses the output was not significantly different from the unaffected group. These findings provide further support for the emerging evidence that preeclampsia with and without SGA may represent two different populations, one with early-onset more severe disease and placental insufficiency and one with late-onset disease without impairment of trophoblast invasion.9–14
In contrast to preeclampsia, maternal cardiac output at 11+0 to 13+6 weeks in pregnancies delivering SGA infants was reduced. Previous studies in pregnancies with SGA fetuses reported that maternal cardiac output was lower than in those with appropriately grown fetuses.42–44 Our findings indicate that this cardiovascular maladaptation is evident from the first trimester of pregnancy and precedes the onset of SGA by several months.
The initial stimulus for the maternal cardiovascular adaptation in early pregnancy is a generalized vasodilatation with secondary compensatory increase in cardiac output.45–47 Although several angiogenic factors or syncytiotrophoblastic particles due to placental apoptosis have been advocated as the trigger for this vasodilatation, at present there is no consensus as to its nature or its mode of action.48,49 On the basis of our results, we could speculate that, in women with SGA, the production of this vasodilatory trigger is impaired, and therefore the maternal cardiovascular system does not have the stimulus to increase cardiac output. In preeclampsia without SGA and in PIH, the placental trigger and/or response may be exaggerated, leading to an increase in cardiac output and a further vasodilatation to accommodate the increased flow.50 When the maximum vessel diameter is reached, a flow-diameter mismatch occurs resulting in hypertension, and when endothelial damage occurs, there is proteinuria and therefore preeclampsia. The findings in the group with preeclampsia and SGA could be the result of an interplay of various degrees of impaired placentation and a concomitant maternal vascular endothelial hyper-responsiveness, as evidenced by the increased risk in this subgroup of women for subsequent development of essential hypertension.51,52 In these pregnancies the reduced plasma volume expansion would lead to an increase in plasma and blood viscosity that would aggravate the effects of impaired placentation on the fetus. In conclusion, in pregnancies complicated by preeclampsia and SGA, there are alterations in maternal central hemodynamics that predate the clinical onset of the disorders and are detectable at 11+0 to 13+6 weeks of gestation.
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© 2008 The American College of Obstetricians and Gynecologists
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