Relationship between maternal hemodynamics and plasma natriuretic peptide concentrations during pregnancy complicated by preeclampsia and fetal growth restriction

Abstract

Objective:

A proper maternal cardiovascular adaptation to the pregnancy plays a key role for promoting an adequate uteroplacental perfusion, for ensuring normal fetal development and for preventing gestational hypertensive complications such as preeclampsia. This study aims to evaluate hemodynamic measurements obtained by noninvasive methods among preclamptic women with and without fetal growth restriction (FGR) and the relationship with plasma levels of natriuretic peptides.

Study Design:

The study compared 98 pregnant women (n=48 with preeclampsia; n=50 normotensive pregnant women) and 50 nonpregnant normotensive control subjects undergoing anultrasonic cardiac output monitor (USCOM) and plasma assessment of atrial N-terminal pro B-type natriuretic peptide (NT-proBNP). The statistical analysis was carried out by analysis of variance and correlation analysis.

Results:

Preeclampsia state is associated with increased vascular resistance (mean 1587±236 vs 978±153 dyn s cm⁻³) and lower cardiac output (mean 5.7±1.1 vs 6.78±0.8 l) and this hemodynamic state is associated with higher levels of NT-proBNP (mean 121.2±26.3 vs 42.5±11.4 pg ml⁻¹); furthermore, we found an inverse correlation between maternal cardiac output and plasma levels of NT-proBNP only if preeclampsia is associated with FGR.

Conclusion:

The elevated NT-proBNP in preeclampsia may reflect ventricular stress and subclinical cardiac dysfunction worsening if FGR is present. This may have implications for the acute management of the preeclampsia and FGR women and for appropriately timed therapeutic interventions later in life.

Introduction

During normal pregnancy, the plasma volume and cardiac output both expand by 50%, whereas the increase in red cell mass is 30%, resulting in a fall in hemoglobin concentration.^{1, 2} A proper maternal cardiovascular adaptation to the pregnancy plays a key role for promoting an adequate uteroplacental perfusion, for ensuring normal fetal development and for preventing gestational hypertensive complications, such as preeclampsia.^{3, 4, 5, 6} In fact, preeclampsia is associated with decreased intravascular volume and increased vasospasm resulting in lower cardiac output and higher vascular resistances, and the increase in peripheral vascular resistance causes an elevation in blood pressure.^{4, 7} Intrauterine growth restriction and preeclampsia are closely linked with abnormal placentation,⁸ and it has been reported that maternal cardiovascular maladaptation appears to be correlated with the occurrence of fetal growth restriction (FGR).^{9, 10} In addition, preeclampsia represents a model of acute pressure overload that may induce changes in the left ventricular function and structure.^{11, 12, 13, 14} Natriuretic peptides are polypeptide hormones produced by the heart and are increased in cardiac overload.^{15, 16} The atrial natriuretic peptides have been suggested as an index for predicting left ventricular diastolic function in preeclampsia.^{15, 17, 18} B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide that is co-secreted with the inactive N-terminal pro B-type natriuretic peptide (NT-proBNP) from the left and right cardiac ventricle in response to ventricular volume expansion and pressure overload. The cardiovascular action of BNP includes vasodilation, diuresis, inhibition of renin and aldosterone production and reduction of cardiac and vascular growth.¹⁹ Results of most studies indicate that circulating levels of NT-proBNP are higher in healthy pregnancies compared with controls and are higher in preeclampsia than in normotensive pregnancies, although not all studies agree.^{15, 20, 21} Seong et al.³⁴ reported that in patients with mild and severe preeclampsia, NT-proBNP levels are elevated; this may reflect ventricular stress and subclinical cardiac dysfunction associated with preeclampsia.

The aim of this prospective observational study was to investigate the association between the maternal cardiac function, using an ultrasonic cardiac output monitor and NT-proBNP as biomarkers in pregnancies complicated by preeclampsia with and without intrauterine FGR in comparison with normal pregnancies and with a non pregnant state.

Methods

Patients

We studied a population of 100 consecutive pregnant women, at the third trimester of pregnancy, 50 with preeclampsia and 50 with normal blood pressure values, gestational week matched. Pregnant women were caucasic, singleton and primigravidas and had normal electrocardiograms, and those with cardiac or renal diseases or diabetes or fetal anomalies were excluded. The patients were recruited from women consecutively admitted to outpatient visits to the Department of Obstetrics and Gynecology of the Polytechnic University of Marche between January 2014 and December 2015 for occasional detection of blood pressure abnormalities among subjects known to have been normotensive before pregnancy. According to the International Society for the Study of Hypertension in Pregnancy (ISSHP), preeclampsia was defined as a blood pressure of at least 140/90 mm Hg, on two occasions 4–6 h apart, after week 20 of gestation in previously normotensive women, accompanied by proteinuria ⩾300 mg/24 h.^{23, 24} Normotensive pregnant subjects were healthy outpatients who routinely attended the antenatal clinic at the same Department and were matched with patients with preeclampsia for maternal and gestational age. None of the patients were being treated with cardiovascular drugs at the time of examination, and all had unrestricted intakes of sodium and potassium. According to the previously described criteria, preeclampsia patients were divided into two subgroups: with and without FGR. FGR was defined as estimated fetal weight and confirmed birth weight of <10th centile.

The pregnant women were compared with a control group of 50 normotensive nonpregnant, age-matched women recruited from personnel of the Department of Obstetrics and Gynecology of Polytechnic University of Marche.

The managing clinicians were blinded to the study results.

The study protocol was approved by the local institutional review committee and written informed consent was obtained from each woman before inclusion.

Cardiac assessment

To measure the cardiac output and total vascular resistances, USCOM was used (USCOM Pty Ltd, Sydney, Australia). This continuous-wave Doppler technique determines blood flow velocity and subsequently calculates the hemodynamic profile. The continuous-wave Doppler obtains velocity time integrals of transaortic or transpulmonary blood flow at the left or right ventricular outflow tract, respectively. All measurements were performed in the supine position. A transducer (3.3 MHz) is positioned in the suprasternal notch with the ultrasound beam directed toward the aortic outflow tract. By gradually adjusting the position of the probe, the highest velocity was measured corresponding to the main systolic flow profile on the visual display of the USCOM. We did not use cardiac index (cardiac output corrected for body surface area) for presentation of our data because use of cardiac index in pregnancy is controversial.²⁴

In the group of women with preeclampsia diagnosis, the cardiac assessment was performed before the starting of any drug treatment. A single medical operator (AP), blinded to the study groups, performed and analyzed all USCOM images and excluded poor-quality Doppler profiles. The operator received formal training for the use of USCOM before recruiting patients to this study.

Laboratory assay

One venous blood sample (10 ml) was drawn from each woman into tubes containing EDTA. Immediately after sampling, plasma was separated by centrifugation at 4 °C for 10 min at 3000 g frozen at –80 °C until assayed (used only once latest 1 month after).

Plasma NT-proBNP levels were assessed using a validated electrochemiluminescence immunoassay (Elecsys proBNP, F. Hoffman-La Roche, Basel, Switzerland) on an Elecsys 2010 analyzer.

Results

A total of 48 women with preeclampsia, 50 women with normal pregnancies and 50 nonpregnant women were included in the study. Cases and controls did not differ significantly for maternal age and gestational age at assessment, but the women with preeclampsia had significantly higher prepregnancy body mass index than controls (Table 1). As expected, women with preeclampsia had higher systolic and diastolic blood pressure and lower gestational age at delivery and centile birth weight (Table 1). In the preeclamptic group the termination of pregnancy was decided for maternal or fetal worsening of clinical conditions, and no significant differences were noted with respect to the motivation of preterm birth. In cardiac assessment, total vascular resistance was significantly lower in normal pregnancy than in nonpregnancy group, and was significantly higher in preeclampsia than in normal pregnancy group (Table 1). The cardiac output was significantly higher in normal pregnancy group versus nonpregnant group and also versus preeclampsia group. Plasma NT-proBNP levels were significantly higher in normal pregnancy versus nonpregnancy and was significantly higher in preeclampsia versus normal pregnancy (Table 1).

Table 1 Obstetrics and cardiac characteristics at sampling

In the comparison between 31 preeclamptic patients without FGR and 17 preeclamptic patients with FGR, higher blood pressure values and lower gestational age at delivery and birth weight centile were observed. In cardiac assessment, total vascular resistance was higher, cardiac output was lower and plasma levels of NT-proBNP were higher (Table 2). In the correlation analysis, cardiac output was significantly inversely related to NT-proBNP only in the preeclampsia with FGR group (Figures 1 and 2, and in the same group, plasma levels of NT-proBNP were inversely related to birth weight centile (Figure 3).

Table 2 Obstetrics and cardiac characteristics in preeclamptic patients

Figure 1

Correlation between maternal cardiac output and maternal plasma NT-proBNP in preeclampsia group. NT-proBNP, N-terminal pro B-type natriuretic peptide.

Figure 2

Correlation between maternal cardiac output and maternal plasma NT-proBNP in preeclampsia with FGR subgroup. FGR, fetal growth restriction; NT-proBNP, N-terminal pro B-type natriuretic peptide.

Figure 3

Correlation between maternal NT-proBNP and birth weight centile in preeclampsia with FGR subgroup. FGR, fetal growth restriction; NT-proBNP, N-terminal pro B-type natriuretic peptide.

Discussion

In a normal pregnancy the increase in maternal cardiac output is accompanied by a decline in mean arterial pressure and a reduction in systemic vascular resistance. This decrease in systemic resistance is evident in the gestational week 5, with 85% of the reduction complete by the gestational week 16.^{25, 26} Disorders of circulatory adaptation in pregnancy such as preeclampsia affect normal maternal hemodynamics and may impact the placental bed, resulting in FGR.²⁷

The principal findings of this study are that the preeclampsia state is associated with increased vascular resistance and lower cardiac output and this hemodynamic state is associated with higher levels of NT-proBNP; furthermore, we found an inverse correlation between maternal cardiac output and plasma levels of NT-proBNP only if preeclampsia is associated with FGR.

In this study we assessed maternal hemodynamics with USCOM device that has been reported to be a potential tool for obtaining a quick and reliable hemodynamic profile in pregnant women.^{22, 28} This technique is reliable when compared with Swan-Ganz pulmonary artery catheter, the gold standard in cardiac surgery patients.²⁹ These conclusions were further corroborated by other studies in postcardiac surgery patients.³⁰

In the same way, natriuretic peptides levels have been proposed to be used as a cost-effective prescreening tool for left ventricular dysfunction. Borghi et al.¹⁸ showed significant increases in left ventricular mass and left ventricular end-systolic and end-diastolic volumes in echocardiograms in preeclamptic patients compared with normotensive pregnant and nonpregnant women. This study also showed significant reductions in left ventricular ejection fraction and percentage of fractional shortening.

NT-proBNP is regarded as a sensitive marker discerning early cardiac dysfunction and has been found to correlate with volume expansion and pressure overload. NT-proBNP levels are related to the left ventricular dysfunction severity stages, thus reflecting the intracardiac pressure and subsequently the cardiac impairment degree.³¹ We found elevated levels of NT-pro-BNP in women with preeclampsia who otherwise had no other cardiovascular risk factors, in line with previous studies.³² The new insight of this study is that the maternal hemodynamic state in preeclampsia is worsening if a FGR is present and in particular the cardiac output is inversely related to levels of NT-proBNP and NT-proBNP is inversely related to birth weight. Thus we believe that the elevated NT-proBNP in preeclampsia may reflect ventricular stress and subclinical dysfunction. Even if the cardiac dysfunction in preeclamptic women is clinically asymptomatic, a significant proportion of women demonstrate asymptomatic left ventricular diastolic chamber dysfunction and essential hypertension within 2 years of delivery.^{14, 33}

Furthermore, previous studies reported that women with preeclampsia have increased risk of developing cardiovascular disease in the future as described in a meta-analysis study by Bellamy et al.¹ The risk is much higher in those with an early-onset compared with the late-onset preeclampsia^3536–37 and when a FGR is present.^{38, 39}

One potential restriction of the present study is the relatively small sample size; it is because of the extremely rigorous inclusion criteria that makes it difficult to enroll a huge number of patients. Given the study design of assessment at disease presentation, it is not possible to ascertain whether these hemodynamic characteristics are a cause or effect of the pregnancy pathologies, but this may have implications for the acute management of the women with preeclampsia and/or FGR and for appropriately timed therapeutic interventions later in life.