Early-pregnancy changes in cardiac diastolic function in women with recurrent pre-eclampsia and in previously pre-eclamptic women without recurrent disease

Authors


Dr SJS Sep, Department of Internal Medicine, The Maastricht Study, PO Box 616, 6200 MD Maastricht, the Netherlands. Email s.sep@mumc.nl

Abstract

Please cite this paper as: Sep S, Schreurs M, Bekkers S, Kruse A, Smits L, Peeters L. Early-pregnancy changes in cardiac diastolic function in women with recurrent pre-eclampsia and in previously pre-eclamptic women without recurrent disease. BJOG 2011;118:1112–1119.

Objective  To compare early-pregnancy changes in cardiac diastolic function between formerly pre-eclamptic women with (RECUR) and without (NORECUR) recurrent pre-eclampsia.

Design  Retrospective observational cohort study.

Setting  Tertiary referral centre.

Population  Pregnant women with a history of early-onset pre-eclampsia (= 34).

Methods  The peak mitral filling velocity in early diastole (E) and at atrial contraction (A), and the E/A ratio were assessed before and at 12, 16 and 20 weeks of gestation in the next pregnancy. Differences in early-pregnancy alterations between women with (RECUR) and without (NORECUR) recurrent pre-eclampsia were evaluated by use of mixed design analysis of covariance.

Main outcome measures  Cardiac function and recurrent pre-eclampsia.

Results  In ten women (29%) pre-eclampsia recurred. By 12 weeks of gestation the E/A ratio had increased in the RECUR group, but not in the NORECUR group (P < 0.01). Moreover, from 16 weeks of gestation onwards, the RECUR group had a lower cardiac output and higher systemic vascular resistance as compared with the NORECUR group (P < 0.05).

Conclusion  Our results suggest that formerly pre-eclamptic women destined to develop recurrent pre-eclampsia differ from their counterparts who do not develop recurrent pre-eclampsia by impaired first-trimester adaptation of cardiac diastolic function.

Introduction

In normal pregnancy, systemic vascular adaptation starts early with a fall in vascular tone, resulting in an approximately 30% decline in systemic vascular resistance.1–3 As the latter tends to decrease cardiac pre- and postloads, the sympathetic contribution to the autonomic control of the circulation increases.4 The fall in systemic vascular tone also activates the volume regulatory system, giving rise to accelerated volume retention.4 These compensations, which raise cardiac output and plasma volume, are paralleled by renal hyperfiltration, haemodilution and activation of the renin–angiotensin–aldosterone system, eventually resulting in the activation of high-flow and low-resistance circulation.1,5–7

Data on the concomitant changes in cardiac function are scarce. Pregnancy-related higher tidal volumes during spontaneous breathing influence cardiac function as a result of exaggerated changes in cardiac pre- and postload.8 Pre-eclampsia is an important cause of maternal and fetal morbidity and mortality worldwide.9 It has been shown to be preceded by impaired early-pregnancy haemodynamic and cardiac adaptation.10 However, whether maladaptation of the cardiac diastolic function to pregnancy is involved in its pathophysiology is currently unknown.

Our study cohort consisted of women with previous early-onset pre-eclampsia. They have an increased risk of recurrence in the next pregnancy.11 Our objective was to evaluate whether the adaptation of the cardiac diastolic function to this next pregnancy differs between women who develop recurrent pre-eclampsia and those who do not. If so, this phenomenon may offer opportunities for future prediction or counselling.

Methods

This is a longitudinal observational cohort study performed at Maastricht University Medical Centre in the Netherlands, in which we observed 34 women with a history of early-onset pre-eclampsia, and compared the adaptation of cardiac diastolic function in the first 20 weeks of the next pregnancy between those who subsequently had and those who had not developed recurrent pre-eclampsia.

All measurements originate from high-risk care provided to women with a history of early-onset pre-eclampsia (diagnosis at ≤34 weeks of gestation, and with delivery at ≤37 weeks of gestation). This high-risk care consists of a pre-conceptional check-up (at least 6 months after the first delivery) combined with medical check-ups at 12, 16 and 20 weeks of gestation. The study protocol was approved by the institutional medical ethical committee.

All women who had completed at least three check-ups and delivered between March 2002 and December 2009 were included. Four women were excluded from the analysis because they had not yet delivered their babies, and two were excluded because two or more check-ups were missing. Furthermore, we excluded one woman with a twin pregnancy and one because of chronic renal failure. Eventually, 34 women with a history of early-onset pre-eclampsia completed a subsequent pregnancy, and were included in the analysis.

Pre-eclampsia was defined according to the guidelines of the National Working Group on High Blood Pressure in Pregnancy: hypertension (blood pressure >140/90 mmHg, occurring after 20 weeks of gestation) accompanied by proteinuria (>300 mg/24 hours or >30 mg/mmol creatinine).12 Pre-eclampsia superimposed on chronic hypertension was defined as new-onset proteinuria after 20 weeks of gestation. All women with chronic hypertension took antihypertensive medication. A birthweight below the tenth percentile, based on the most recent Dutch birthweight reference curves,13 was used to classify infants as small for gestational age (SGA).

Echocardiography was performed with the patient in left-lateral position, after 5 minutes of rest, with an S5–1 phased array transducer (bandwidth 5–1 MHz) interfaced with a Philips IE33 system (Philips Medical Systems, Best, the Netherlands). Pulsed wave (PW) Doppler-derived transmitral velocities were obtained at the mitral leaflet tips according to the guidelines of the American Society of Echocardiography.14 From the parasternal long-axis view we performed the following measurements: left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septal end-diastolic wall thickness, posterior wall end-diastolic wall thickness and left atrial diameter (LAD), according to criteria of the American Society of Echocardiography.15 The diameter of the inferior caval vein was measured from a substernal M-mode recording. The left ventricular mass was calculated by the Devereux formula.16 The left atrial volume was measured in apical four- and two-chamber views at mitral valve closure using the biplane method of discs.17 In the apical four-chamber view, the right atrial volume was estimated using the area–length formula.18 Cardiac dimensions were indexed to body surface area. All data were stored digitally and calculations were performed offline using dedicated software (XCELERA; Philips, Amsterdam, the Netherlands) by a single observer, who was blinded to the clinical data.

Left ventricular function was assessed using the Teicholz formula applied to ventricular diameters measured parasternally, resulting in a left ventricular ejection fraction.19 Cardiac output (CO, l/min) was obtained by multiplying stroke volume (SV) with heart rate (HR). The HR was obtained by taking the reciprocal of the mean of between three and five consecutive R–R intervals (the time measurement between the R-wave of one heartbeat and the R-wave of the preceding heartbeat) on the electrocardiogram. From an apical approach, aortic flow across the aortic valve was measured using continuous wave (CW) Doppler. SV was calculated by multiplying the aortic velocity time integral (VTI) with the cross-sectional area measured at the level of the aortic annulus in the parasternal long-axis view. The mean VTI, used to calculate SV, was measured by averaging the outer edge tracings of between three and five consecutive CW Doppler registrations.

Diastolic function was measured using PW Doppler echocardiography to obtain transmitral flow determined from the apical four-chamber view. The PW Doppler sample volume (5 mm) was carefully positioned at the tip of the mitral valve leaflets. The sweep rate was set at 50 mm/s. We defined the E/A ratio as the ratio of peak mitral flow velocity in early diastole (E) with that during atrial contraction (A). In addition, the E-wave deceleration time was measured. Doppler-derived indices were averaged from between three and five consecutive cardiac cycles.

Blood pressure was recorded in standardized environmental conditions, with external disturbances kept to a minimum and the subject in left-lateral tilt position with a rolled blanket placed under the left side of her back. Participants did not eat for at least 10 hours prior to the measurement. We registered blood pressure every 3 minutes, using a semiautomatic oscillometric device (Dinamap Vital Signs Monitor 1846; Critikon, Tampa, FL, USA) over a period of 30 minutes.

We used SPSS v15.0.0 (SPSS, Inc., by IBM, Somers, NY, USA) for the statistical analysis. The normality of cardiac function data was checked graphically by histograms. Non-normally distributed data were transformed logarithmically. To evaluate the response of the cardiac diastolic function to pregnancy and differences in this response between groups we used mixed design analysis of variance (ANCOVA). As with any ANCOVA, the repeated-measures ANCOVA tests the equality of means. However, a repeated-measures ANCOVA is used when all subjects are measured under a number of different conditions (in this study, different gestational ages). Using a standard ANCOVA in this case is not appropriate because it fails to model the correlation between the repeated measures. The analysis has a mixed design because it includes both within- and between-subject variables. The within-subject variables in our analysis are: the E/A ratio, the E-wave velocity, the A-wave velocity, CO and total peripheral vascular resistance (TPVR), measured at four stages (0, 12, 16 and 20 weeks of gestation). The between-subjects variable is recurrent pre-eclampsia (yes/no). Statistical interaction between the four-stage cardiac function variable and recurrent pre-eclampsia indicates different longitudinal patterns in women with recurrent pre-eclampsia, as compared with those without recurrence. Bonferroni’s adjustment for multiple comparisons was used in testing within-group differences at specific levels. Missing values were inputted using a single imputation regression procedure to avoid listwise deletion.20 Data are presented as means ± SDs, unless otherwise stated. The 95% confidence intervals presented in the figures are corrected for between-subject variability according to the methods of Loftus and Masson.21 All effects are reported as significant at P < 0.05.

Results

Ten (29, 95% CI 13–42%) of the 34 formerly pre-eclamptic women developed recurrent pre-eclampsia (RECUR) in their next pregnancy. The remaining 24 women had no recurrent pre-eclampsia in their next pregnancy (NORECUR). Table 1 lists the pregravid demographic, clinical and obstetric characteristics of the women in both subgroups. The groups did not differ from one another with respect to mean arterial pressure, chronic hypertension, smoking status and parity. None of the women had diabetes mellitus. The mean maternal age, body mass index (BMI) and height values were lower in the RECUR group (P = 0.07, 0.17 and 0.01, respectively). Characteristics of the previous pregnancy were not statistically significantly different between both groups, although the duration of pregnancy in the RECUR group was on average 1 week shorter, with a higher frequency of very preterm births (at <32 weeks of gestation), and with a median birthweight 100 g lower, compared with the NORECUR group. Table 2 lists clinical characteristics of the next pregnancy. A comparable fraction of both study groups used antihypertensive medication (either Aldomet or Labotalol) throughout the study period. The gestational age at birth was approximately 5 weeks shorter in the RECUR group, and birthweight was 1 kg lighter than in the NORECUR group. Tables 3 and 4 list the mean pre-pregnancy values for cardiac dimensions and cardiac function variables. None of these variables differed appreciably between the RECUR and NORECUR groups at baseline.

Table 1.   Pregravid demographic, clinical and obstetric history characteristics of formerly pre-eclamptic women with (RECUR) and without (NORECUR) recurrent pre-eclampsia in their next pregnancy
VariableRECUR
(n = 10)
NORECUR
(n = 24)
P
  1. Data are presented as means ± SDs, n (%) or medians (IQR).

  2. Maternal age at 12 weeks of gestation.

  3. BMI, body mass index; IUFD, intrauterine fetal demise.

  4. Standard chi-square test, independent Student’s t-test and Mann–Whitney U-test were used.

Maternal age (years)30 ± 533 ± 50.07
BMI (kg/m2)24.5 ± 3.527.0 ± 5.20.17
Height (cm)164 ± 4169 ± 60.01
Mean arterial pressure (mmHg)96 ± 794 ± 150.66
Chronic hypertension3 (30%)6 (25%)0.76
Smoking1 (10%)1 (4%)0.51
Multiparity1 (10%)1 (4%)0.51
Gestational age previous birth (weeks)29.6 ± 2.930.6 ± 3.80.49
Very preterm birth (<32 weeks)8 (80%)15 (63%)0.32
Birth weight of previous child (g)890 (599–1348)990 (615–1680)0.46
Very low birth weight (<1500 g)8 (80%)17 (71%)0.58
Previous SGA newborn (<p10)4 (40%)10 (42%)0.93
IUFD in previous gestation3 (30%)7 (29%)0.96
Time between delivery and first measurement (months)8 (6–25)12 (7–31)0.38
Interbirth interval (months)24 (18–43)35 (18–39)0.89
Table 2.   Obstetric characteristics of formerly pre-eclamptic women with (RECUR) and without (NORECUR) recurrent pre-eclampsia in their next pregnancy
VariableRECUR
(n = 10)
NORECUR
(n = 24)
P
  1. Data are presented as means ± SDs, n (%) or medians (IQR).

  2. Standard chi-square test, independent Student’s t-test and Mann–Whitney U-test were used.

Antihypertensive medication at preconception check-up3 (30%)6 (25%)0.71
Antihypertensive medication at 12 weeks of gestation4 (40%)7 (29%)0.36
Antihypertensive medication at 16 weeks of gestation5 (50%)10 (42%)0.41
Antihypertensive medication at 20 weeks gestation5 (50%)11 (46%)0.54
Gestational age at birth (weeks)34.2 ± 4.639.3 ± 1.5<0.01
Birthweight (g)2413 (1083–2938)3300 (3064–3645)<0.01
SGA newborn5 (50%)5 (21%)0.09
Table 3.   Pregravid (baseline) cardiac dimensions for ten formerly pre-eclamptic women who developed recurrent pre-eclampsia in their subsequent pregnancy (RECUR), and for 24 formerly pre-eclamptic women who did not (NORECUR)
VariableRECUR
(n = 10)
NORECUR
(n = 24)
P
  1. Data are presented as means ± SDs.

  2. The independent Student’s t-test was used.

  3. All cardiac dimensions were indexed to body surface area (m2).

Left atrium diameter (mm)2.0 ± 0.21.8 ± 0.10.12
Left atrium volume (ml)30.9 ± 7.5230.4 ± 5.80.82
Left ventricular mass (g)74.3 ± 12.477.2 ± 11.00.51
Left ventricular end-diastolic diameter (mm)26.1 ± 2.525.1 ± 2.20.22
Left ventricular end-systolic diameter (mm)16.8 ± 1.816.7 ± 1.70.79
Vena cava diameter (mm)7.9 ± 1.89.3 ± 2.30.10
Table 4.   Pregravid (baseline) cardiac function variables for ten formerly pre-eclamptic women who developed recurrent pre-eclampsia in their subsequent pregnancy (RECUR), and for 24 formerly pre-eclamptic women who did not (NORECUR)
VariableRECUR
(n = 10)
NORECUR
(n = 24)
P
  1. Data are presented as means ± SDs.

  2. The independent Student’s t-test was used.

Peak E-wave velocity (cm/s)80.5 ± 13.685.4 ± 12.70.32
Peak A-wave velocity (cm/s)58.8 ± 10.958.4 ± 9.10.91
E/A ratio1.4 ± 0.31.5 ± 0.30.60
E deceleration time (s)0.15 ± 0.30.17 ± 0.040.27
Cardiac output (l/min)5.12 ± 0.785.25 ± 0.880.68
Stroke volume (ml)68.3 ± 11.273.7 ± 12.80.26
Heart rate (bpm)76.2 ± 16.672.5 ± 14.00.51
TPVR (dynes s/cm5)1532 ± 2491477 ± 3250.64

Overall, 4% of the longitudinal data were imputed because of missing values. Cardiac function data appeared to be normally distributed. The pregnancy-induced changes in E/A ratio are displayed in Figure 1. As opposed to no appreciable first-trimester change in E/A ratio in the NORECUR group, we observed a consistent rise in this ratio in the RECUR group (P < 0.01 for interaction, first 12 weeks of gestation). The latter resulted from a trend towards a steeper rise in E-wave velocity relative to the NORECUR group (P = 0.09 for interaction), along with a trending fall in A-wave velocity (P = 0. 21 for interaction). By contrast, in the NORECUR group, pregnancy had induced a consistent rise in the A-wave velocity, on average by 4.9 ± 1.8 cm/second (P = 0.05) (Figure 1). An increase in the E/A ratio of more than 7% by 12 weeks of gestation (cut-off estimated by receiver operating characteristic curve) indicated an increased risk for recurrent pre-eclampsia (relative risk 4.80, 95% CI 1.86–12.37). The responses of the E deceleration time and left atrial diameters and volumes to pregnancy did not differ between the groups.

Figure 1.

 Mean and 95% confidence intervals (corrected for between-subjects variability) of the E/A ratio in the first 20 weeks and the E- and A-wave velocities in the first 12 weeks of gestation in women who developed recurrent pre-eclampsia (black), and for those who did not (grey). In the first 12 weeks of gestation, the pattern of change in the E/A ratio differed between groups (P < 0.01), mainly because of a different adaptation in the A-wave velocity (P = 0.02).

Figures 2 and 3 show the changes in cardiac output and total peripheral vascular resistance in the first 20 weeks of gestation. From 16 weeks onwards, cardiac output was lower and systemic vascular resistance was higher in the RECUR group, compared with the NORECUR group (P < 0.05).

Figure 2.

 Mean and 95% confidence intervals (corrected for between-subjects variability) of cardiac output (CO) in the first 20 weeks of gestation in women who developed recurrent pre-eclampsia (black) and those who did not (grey). From 16 weeks of gestation onwards intergroup differences were significantly different (P < 0.05).

Figure 3.

 Mean and 95% confidence intervals (corrected for between-subjects variability) of TPVR in the first 20 weeks of gestation in women who developed recurrent pre-eclampsia (black) and those who did not (grey). From 16 weeks of gestation onwards intergroup differences were significantly different (P < 0.05).

Discussion

Our results indicate that formerly pre-eclamptic women destined to develop recurrent disease in their next pregnancy differed from their counterparts with no recurrent disease by a rise in the E/A ratio in the first trimester, together with a lower cardiac output and higher peripheral vascular resistance between 16 and 20 weeks of gestation. In the recurrence group, the first-trimester increase in E/A ratio resulted from a tendency of increasing E-wave velocity along with a decreasing A-wave velocity. By contrast, in women without recurrent disease both E- and A-wave velocities had increased in response to pregnancy, resulting in an absent initial change in the E/A ratio.

When blood flow across the mitral valve is assessed by pulsed-wave Doppler, two waves are characteristically seen. These represent the passive filling of the ventricle [early (E) wave] and the active filling during atrial systole [atrial (A) wave]. Classically, the E-wave velocity is slightly greater than that of the A wave. However, in conditions that limit the compliance of the left ventricle, abnormalities are possible.

The mitral E-wave velocity primarily reflects the pressure gradient between the left atrium and the left ventricle during early diastole. The E-wave velocity is thus affected by both the preload and alterations in left ventricular relaxation. Meanwhile, the mitral A-wave velocity reflects the left atrium–left ventricle pressure gradient during late diastole, which is affected by left ventricular compliance and left atrium contractile function.

During normal pregnancy, there is a reversible shift in transmitral flow velocities from early to late filling, leading to a decreased E/A ratio in late pregnancy. This is strongly related to physiological changes in HR, preload, left ventricular compliance and contractility, as well as to gestational age.22 The increase in A-wave velocity observed in the NORECUR group is in line with previous findings,23,24 but is in contrast to others,25 and is consistent with enhanced left atrium contraction in the face of the pregnancy-induced increase in left atrium preload and left ventricular compliance.26

In diastolic dysfunction, the atrial contribution to left ventricular filling is reduced because of impaired left ventricular relaxation and increased left ventricular end-diastolic filling pressures.27,28 A parallel between diastolic dysfunction and pre-eclampsia should be drawn with caution. Nevertheless, the steeper increase in E-wave velocity observed in the RECUR group during early pregnancy, together with a trend in A-wave velocity to decline, might reflect impaired relaxation and higher left ventricular end-diastolic filling pressures because of increased left ventricular stiffness in these women.

In a previous study, early cardiac adaptation to pregnancy was found to differ between formerly pre-eclamptic women with subnormal (≤48 ml/kg lean body mass) and normal plasma volume.1 In the present study, the proportions of women with subnormal plasma volume were similar in the RECUR and NORECUR groups (60 versus 55%, respectively), indicating that plasma volume had not influenced the effects observed.

Despite the small sample size, our observations uniquely address the initial pregnancy-induced changes in cardiac function. Although pre-eclampsia does not become clinically manifest before the 20th week of pregnancy, in many cases the pathogenesis of pre-eclampsia seems to begin early in gestation. Therefore, in addition to preconception prediction and counselling, formerly pre-eclamptic women may benefit from early-pregnancy recurrence risk prediction. This study was conducted to find clues for potential differences in the early adaptation of cardiac function between formerly pre-eclamptic women who do and do not develop recurrent pre-eclampsia in their next pregnancy. For this reason, we did not include ‘normal’ pregnant women, and nor did we define a control group of women with no complications.

Limitations

Although our results should be interpreted with caution because mitral E-wave and A-wave velocities are load dependent, this is not easily controlled for. However, a clear dissociation of diastolic function between the RECUR and the NORECUR groups is already apparent in this small study group. The non-invasive assessment of cardiac diastolic function by echocardiography is complex. Besides the basic parameters reported in this study, more sophisticated, less load dependent, methods exist to determine left ventricular diastolic function, based on the integrative analysis of transmitral Doppler flow, pulmonary venous flow, colour M-mode velocity propagation and tissue Doppler imaging (TDI). More detailed assessment of pregnancy-induced responses of the cardiac diastolic function in future studies is to be encouraged.29

The use of the Dinamap 1846 oscillometric blood pressure monitor may have resulted in systematically underestimated blood pressure and TPVR.30–34 As our aim was to evaluate changes over time, we do not believe this drawback has influenced our results and conclusions. However, cross-sectional blood pressure values and TPVR should be interpreted with caution.

Conclusion

In summary, we found that cardiac adaptation to pregnancy in formerly pre-eclamptic women who developed recurrent pre-eclampsia in their next pregnancy differed from their counterparts who did not. Formerly pre-eclamptic women showed an initial rise in the E/A ratio, which is consistent with an initially impaired adaptation of the cardiac diastolic function. In the recurrence group this phenomenon was followed by a lack of increase in cardiac output in concert with a rise in systemic vascular resistance, providing indirect evidence for a higher sympathetic contribution to the autonomic control of the circulation in the second trimester. The latter supports the view that impaired adaptation of the cardiac diastolic function might be an important contributor to the subnormal cardiovascular adaptation to pregnancy preceding overt pre-eclampsia.

Disclosure of interests

We declare that we have no conflict of interests.

Contribution to authorship

SJSS and MPHS performed the statistical analysis and wrote the article. MPHS also managed the data. SCAMB and AJK gave advice with regards to the content and participated in writing the article. LJS and LLHP helped to design the study, to statistically analyse the data and to revise the article.

Details of ethics approval

The procedures of this study received ethics approval (May 2010, MEC 10-4-049) from the medical ethical committee university hospital Maastricht/Maastricht University (MEC azM/UM).

Funding

The research institutes GROW (School for Oncology and Developmental Biology) and CAPHRI (School for Public Health and Primary Care) of Maastricht University, Faculty of Health, Medicine and Life Sciences contributed to this study financially.

Acknowledgements

We thank T Ekhart for the collection and entry of the data and F Prinzen for sharing his knowledge on cardiac physiology.

Ancillary