Does pre-eclampsia influence fetal cardiovascular function in early-onset intrauterine growth restriction?

Authors

  • F. Crispi,

    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • M. Comas,

    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • E. Hernández-Andrade,

    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • E. Eixarch,

    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • O. Gómez,

    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • F. Figueras,

    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • E. Gratacós

    Corresponding author
    1. Maternal–Fetal Medicine Department, Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Hospital Clinic, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    • Department of Maternal–Fetal Medicine (ICGON), Hospital Clínic, Sabino de Arana 1, 08028, Barcelona, Spain
    Search for more papers by this author

Abstract

Objectives

Increasing evidence shows that intrauterine growth restriction (IUGR) is associated with fetal cardiac dysfunction. Most studies group IUGR with and without pre-eclampsia (PE) altogether. Our objective was to evaluate whether the association with PE has any impact on cardiac function in IUGR fetuses

Methods

Thirty-one normotensive IUGR cases and 31 IUGR cases with pre-eclampsia (PE + IUGR) below 34 weeks of gestation were included. IUGR was defined as a birth weight below the 10th centile together with an umbilical artery pulsatility index above 2 SD. Fetal cardiac function was assessed by measuring ductus venosus pulsatility index, modified myocardial performance index, aortic isthmus blood flow, E/A ratios and cardiac output. The presence of fetal cardiac dysfunction was also assessed by measuring cord blood B-type natriuretic peptide (BNP) levels collected at birth. Echocardiographic data were compared with those in 80 term appropriate-for-gestational age (AGA) fetuses from normotensive mothers. Cord blood BNP levels were compared with those in 40 AGA cases that delivered preterm.

Results

All IUGR cases (with or without PE) showed echocardiographic and biochemical signs of cardiac dysfunction compared with AGA cases. However, no differences were observed between IUGR and PE + IUGR cases either in echocardiographic or in biochemical parameters. IUGR cases with or without PE had similar perinatal results.

Conclusions

IUGR fetuses showed echocardiographic and biochemical signs of cardiac dysfunction. Pre-eclampsia per se does not influence cardiac function in IUGR fetuses. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.

Introduction

Intrauterine growth restriction (IUGR) affects 1–3% of all pregnancies and constitutes an important cause of perinatal mortality and morbidity1. Increasing evidence shows that IUGR is associated with fetal cardiovascular dysfunction. Several studies have reported significant differences in echocardiographic parameters, mainly related to diastolic function2, 3, and raised fetal levels of B-type natriuretic peptide (BNP)3, 4. The presence of abnormal cardiac function is associated with poorer perinatal outcome in IUGR fetuses3, 5, 6 and this has prompted research on new cardiovascular parameters that might improve in-utero monitoring7. In addition, epidemiological studies and animal models have established that babies of low birth weight have an increased risk of developing cardiovascular disease later in life, including hypertension and coronary disease8. Thus, characterization of fetal cardiac dysfunction may be relevant for clinical management and for the understanding of fetal cardiac programming.

A potential concern in the interpretation of studies on fetal cardiovascular function in IUGR is the common association with pre-eclampsia (PE)9–12. Most studies on cardiovascular assessment in IUGR have included, without distinction, pregnancies with and without this condition13. PE is characterized by dysfunction of the maternal vascular endothelium, which leads to increased systemic vascular resistance and maternal hemodynamic changes14, 15. Several studies have shown that PE is also associated with features of endothelial dysfunction in the fetus16, 17. It is unknown to what extent these changes have any influence on fetal cardiovascular function.

The aim of this study was to evaluate whether the association with PE has any impact on cardiovascular function in preterm IUGR fetuses with a comparable degree of peripheral Doppler abnormalities.

Methods

Study populations

The study included 31 normotensive IUGR, 31 IUGR + PE and 120 control appropriate-for-gestational age (AGA) fetuses (80 term AGA and 40 preterm AGA). The study protocol was approved by the local ethics committee and patients provided their written informed consent. Exclusion criteria were structural/chromosomal anomalies or evidence of fetal infection. All IUGR cases and the subgroup of 40 preterm AGA cases were delivered or died at < 34 weeks of gestation. In all pregnancies gestational age was calculated based on the crown–rump length at first trimester ultrasound examination. IUGR was defined as an estimated fetal weight below the 10th centile according to local reference curves18 together with umbilical artery (UA) pulsatility index (PI) above 2 SD19. PE was diagnosed in the presence of hypertension associated with proteinuria20. Hypertension was defined as resting blood pressure ≥ 140 mmHg (systolic) and/or ≥ 90 mmHg (diastolic) on two occasions at least 4 h apart after the 20th week of gestation in women known to be normotensive beforehand. Proteinuria was defined as excretion of 300 mg or more in a 24-h specimen or a 2+ urine dipstick20. Forty-three IUGR cases reported here have been included as part of a previous study3. Preterm delivery in AGA cases was spontaneous preterm delivery or elective delivery for preterm rupture of membranes or bleeding secondary to placenta previa. In all preterm cases infection was ruled out by the absence of clinical signs and negative placental and neonatal cultures.

All IUGR cases underwent Doppler ultrasonographic examination of fetal cardiovascular hemodynamics every 48–72 h until delivery or death. Doppler and cardiovascular parameters obtained at the last examination before death or delivery were used for statistical analysis. The ultrasound studies were performed using a Siemens Sonoline Antares (Siemens Medical Systems, Malvern, PA, USA) or a Voluson 730 Expert (GE Medical Systems, Milwaukee, WI, USA) with 6–4-MHz linear curved-array probes. All estimations were done in the absence of fetal movements and, when required, with the mother in voluntary suspended respiration. An angle of insonation of < 30° between the vessel and the Doppler beam was accepted for analysis. The mechanical and thermal indices were maintained below 1, and the wall filter was set to 70 Hz. Doppler parameters were obtained from three or more successive waveforms in each vessel. Basic Doppler examination included the UA and fetal middle cerebral artery (MCA). UA-PI was measured from a free loop of the umbilical cord. MCA-PI was measured distal to the junction of the internal carotid artery in a transverse view of the fetal skull at the level of the circle of Willis. The cerebroplacental ratio was calculated as MCA-PI/UA-PI. Echocardiographic assessment was also performed at each ultrasound examination.

At delivery, gestational age, birth weight, birth weight centile, Apgar scores and umbilical pH were recorded. Perinatal mortality was defined as either intrauterine death or neonatal death within the first 28 days of postnatal life5. Additionally, cord blood from umbilical vein was collected to measure the concentration of B-type natriuretic peptide (BNP).

Echocardiographic assessment

Cardiovascular function was assessed by ultrasound imaging using two-dimensional B-mode and Doppler ultrasound. Cardiovascular measurements included ductus venosus (DV) PI, aortic isthmus blood flow index (IFI), E/A ratios, left modified myocardial performance index (MPI) and combined cardiac output (CCO).

The DV was measured either in a mid-sagittal view of the fetal thorax or in a transverse plane through the upper abdomen prior to its entrance into the inferior vena cava, positioning the Doppler gate at the DV isthmic portion21. The aortic isthmus was sampled downstream of the left subclavian artery and just upstream of the ductus arteriosus connection in a sagittal view simultaneously visualizing the aortic arch. IFI was calculated by dividing the sum of the systolic and diastolic Doppler flow integrals by the systolic flow integral22. Atrioventricular flows were obtained from a basal or apical four-chamber view, placing the pulsed Doppler sample volume just below valve leaflets. Right and left E/A ratios were estimated by calculating the ratio between early ventricular filling (E-wave) to late ventricular filling (A-wave)23. Left modified MPI was obtained in a cross-sectional image of the fetal thorax, placing the Doppler sample volume on the medial wall of the ascending aorta and including the leaflets of the aortic and mitral valves24, 25. The clicks of the valves registered in the Doppler trace were used as landmarks to calculate the following time periods: isovolumetric contraction time (ICT) from the closure of the mitral valve to the opening of the aortic valve, ejection time (ET) from the opening to the closure of the aortic valve, and isovolumetric relaxation time (IRT) from the closure of the aortic valve to the opening of the mitral valve. Finally, the modified MPI was calculated as (ICT + IRT)/ET. Left and right cardiac outputs were calculated as π × (aortic or pulmonary valve diameter)2 × (aortic or pulmonary artery systolic time–velocity integral) × heart rate. Then, CCO was calculated as the sum of both26. Diameters of the aortic and pulmonary valves were measured three times in frozen real-time images during systole by the leading-edge to leading-edge method and their mean value was used for further analysis. Aortic systolic time–velocity integral was obtained in a long axis of the left ventricle, and pulmonary artery systolic time–velocity integral in a short-axis view of the fetal heart, and were calculated by planimetering the area underneath the Doppler spectrum.

Cord blood sampling and B-type natriuretic peptide assessment

Cord blood samples were collected immediately after delivery. Plasma was separated by centrifugation at 3000 rpm for 10 min at 4 °C, and samples were immediately stored at −80 °C until assayed. Levels of BNP were measured using Siemens ADVIA Centaur® BNP assay27.

Statistical analysis

A sample size of 31 patients in each study group was calculated by expecting differences between cases and controls in MPI and BNP above 20%, for a given 5% α error and 80% power. The case cohort was derived from consecutive IUGR cases attending our institution between January 2006 and December 2007. For each case of the IUGR group, the next patient in the cohort with the diagnosis of IUGR and PE delivering within the same study period at the same gestational age (+/−2 weeks) was selected. Controls were selected randomly from our general population. Two different control populations of AGA fetuses were selected. To compare echocardiographic parameters, 80 controls (term AGA) were selected from consecutive pregnant women attending our department for scan between 24 and 37 weeks of gestational age. In order to compare cord blood levels of BNP, 40 AGA cases delivering between 24 and 36 weeks (preterm AGA) were selected from consecutive preterm deliveries attending our department.

Data were analyzed with the SPSS version 13.0 statistical package (SPSS, Chicago, IL, USA). Ultrasound measurements were converted into Z-scores (SD from the gestational age mean), with the exception of cardiac output which was normalized by estimated fetal weight19, 21–23, 25, 26. Results were expressed as median and interquartile range. Comparisons among groups were performed by ANOVA based on log-transformed data adjusted with Bonferroni's post-hoc test. Finally, to answer the primary question of the study, a Mann–Whitney U-test between IUGR and IUGR + PE cases was performed. Differences were considered significant when P < 0.05.

Results

Characteristics of the study populations

The characteristics of the study populations are reported in Table 1. As expected, IUGR cases with or without PE had higher UA-PI, and lower MCA-PI, cerebroplacental ratio and birth weight percentile compared with term and preterm AGA cases. All perinatal and Doppler parameters were similar among IUGR and IUGR + PE cases. A non-significant trend towards higher perinatal mortality was observed in IUGR compared with IUGR + PE cases. Delivery criteria in IUGR cases were abnormal venous Doppler findings (27 IUGR and 16 IUGR + PE cases), abnormal cardiotocogram or biophysical profile (four IUGR and four IUGR + PE cases) and maternal condition (11 IUGR + PE cases).

Table 1. Characteristics of the study populations
ParameterTerm AGA (n = 80)Preterm AGA (n = 40)IUGR (n = 31)IUGR + PE (n = 31)P*P
  • Data presented as median (interquartile range), except for mortality. Doppler values are expressed in Z-scores.

  • *

    Comparison among groups performed with ANOVA.

  • Comparison between intrauterine growth restriction (IUGR) and IUGR + pre-eclampsia (PE) groups performed with Mann–Whitney U-test.

  • P < 0.05 vs. term appropriate-for-gestational age (AGA).

  • §

    P < 0.05 vs. preterm AGA.

  • PI, pulsatility index.

Maternal characteristics
 Systolic blood pressure (mmHg)110 (20)113 (13)124 (10)168 (38)§< 0.001< 0.001
 Diastolic blood pressure (mmHg)70 (10)69 (7)73 (5)104 (14)§< 0.001< 0.001
 Proteinuria (mg/24 h)137 (100)246 (60)194 (125)1981 (2461)§0.054< 0.001
Basic Doppler results
 Gestational age at ultrasound (weeks)28.5 (7.1)29 (6.2)28.6 (6.3)30 (3.3)0.1170.550
 Umbilical artery mean PI0.01 (1.3)0 (2.04)7 (9)§8 (11.25)§< 0.0010.337
 Middle cerebral artery PI0.1 (1.34)−0.01 (1.23)−2.53 (1)§−2.61 (1.32)§< 0.0010.340
 Cerebroplacental ratio0.07 (1.26)0.03 (1.16)−3.54 (1.41)§−3.08 (0.61)§< 0.0010.065
Perinatal outcome
 Gestational age at delivery (weeks)39 (1)30 (6)31 (4)30 (4)< 0.0010.764
 Birth weight (g)3110 (475)1605 (1087)1030 (470)§995 (274)§< 0.0010.814
 Birth weight percentile45 (38)50 (54)1 (1)§1 (1)§< 0.0010.259
 5-min Apgar score10 (0)10 (1)9 (1)9 (2)0.0160.266
 Cord arterial pH7.30 (0.07)7.27 (0.08)7.21 (0.07)7.22 (0.1)0.2410.706
 Perinatal mortality (%)0319§13  

Echocardiographic assessment

Values of cardiovascular parameters are shown in Table 2 and Figure 1. All measurements with the exception of cardiac output were significantly different in IUGR fetuses (with or without PE) from those in term AGA cases. However, there were no differences between IUGR and IUGR + PE cases.

Figure 1.

Echocardiographic assessment in the term appropriate-for-gestational age (AGA), intrauterine growth restriction (IUGR) and IUGR + pre-eclampsia (PE) groups: ductus venosus pulsatility index (PI) (a), aortic isthmus blood flow index (IFI) (b), right E/A ratio (c), left E/A ratio (d), modified myocardial performance index (MPI) (e) and combined cardiac output (CCO) (f). Data are presented as mean ± SEM. *P < 0.05 vs. term AGA.

Table 2. Echocardiographic parameters in the study populations
ParameterTerm AGA (n = 80)IUGR (n = 80)IUGR + PE (n = 80)P*P
  • Doppler values are expressed in Z-scores, with the exception of combined cardiac output (CCO), which was normalized by fetal weight. Data presented as median (interquartile range).

  • *

    Comparison among groups performed with ANOVA.

  • Comparison between intrauterine growth restriction (IUGR) and IUGR + pre-eclampsia (PE) groups performed with Mann–Whitney U-test.

  • P < 0.05 vs. term appropriate-for-gestational age (AGA).

  • MPI, myocardial performance index; PI, pulsatility index.

Ductus venosus PI0.02 (1)2.3 (4)2.1 (5)< 0.0010.088
Aortic isthmus flow index−0.1 (0.9)−1.7 (8.3)−1.7 (7.1)< 0.0010.118
Left E/A ratio−0.3 (1.4)0.8 (3.4)1.2 (2.9)0.0190.843
Right E/A ratio0.1 (0.9)1.6 (3.1)1.2 (1.4)0.0010.610
Modified MPI−0.4 (1.2)1.8 (2.5)2.1 (3.4)< 0.0010.335
CCO (mL/min/kg)549 (56)751 (279)801 (178)0.9030.400

Cord blood B-type natriuretic peptide

Data on cord blood BNP levels are shown in Figure 2. BNP levels were significantly higher in IUGR with or without PE than in AGA cases. However, BNP concentrations were similar among IUGR cases with or without PE.

Figure 2.

Cord blood B-type natriuretic peptide (BNP) levels in the term appropriate-for-gestational age (AGA), preterm AGA, intrauterine growth restriction (IUGR) and IUGR + pre-eclampsia (PE) groups. Data are presented as mean ± SEM. *P < 0.05 vs. term AGA.

Discussion

This study provides evidence that IUGR fetuses with and without PE have a similar degree of cardiovascular dysfunction, as measured by means of echocardiographic and biochemical parameters. The study groups were comparable in terms of the degree of growth restriction and Doppler deterioration. The data support the concept that PE per se does not have an influence in the presence of cardiovascular dysfunction in IUGR.

The findings confirm previous studies reporting clear evidence of the existence of abnormal cardiovascular function in IUGR. As expected and previously described3, 28, DV-PI was significantly increased in both study groups. To a great extent DV-PI reflects myocardial impaired relaxation29, 30, and it is the strongest predictor of perinatal mortality and morbidity in severe IUGR5, 31. Apart from DV-PI, several ultrasound measurements, including IFI, E/A ratios and MPI, and cord blood BNP levels were abnormal in both study groups. Previous clinical series have reported that IUGR fetuses with aortic isthmus reversed diastolic flow have a deterioration of cardiac function and a poorer perinatal outcome6, 32. The aortic isthmus has a dynamic role in connecting the right and left circulatory systems of the fetus, and has been proposed as a potential monitoring tool for IUGR fetuses6, 32. Left and right E/A ratios have recently been noted to be significantly increased in IUGR with respect to controls3, 4, supporting the existence of abnormal ventricular filling during diastole. MPI, a Doppler index of combined systolic and diastolic function, has been recently shown to be raised in IUGR fetuses3, 33. BNP is a ‘gold standard’ marker for heart failure in adults34 and children35 and has been demonstrated to be increased in IUGR from early stages of fetal deterioration3, 4. Of interest, the study confirmed previous observations indicating that cardiac output is maintained within normal values in IUGR3, 4, 26.

Concerning UA and MCA Doppler indices, similar differences with respect to controls were observed between study groups. Several studies have evaluated fetoplacental Doppler parameters in IUGR fetuses with and without PE. Harrington et al.36, 37 showed a similar pattern of changes in the UA and MCA in preterm small-for-gestational age fetuses with or without PE. More recently, Mari et al.38 showed that IUGR fetuses without PE undergo a series of well defined Doppler changes until fetal deterioration occurs or the fetus is delivered because of non-reassuring testing. On the contrary, IUGR fetuses with PE were often delivered for maternal indication before the full range of Doppler changes occurred38. This may also explain the relatively better fetal outcome in the IUGR + PE group in our study, which may be secondary to an earlier delivery owing to maternal condition, whereas pure IUGR cases are more likely to be delivered only if there are severe signs of fetal decompensation. Therefore, we acknowledge that our results may have been affected by selection bias.

Although perinatal outcome was similar in IUGR cases with or without PE, a non-significant trend towards higher perinatal mortality in normotensive IUGR fetuses was observed in this study. This finding is consistent with a previous report by Piper et al.39 that included 1012 preterm small-for-gestational age cases and showed that perinatal mortality was significantly higher in the normotensive than in the hypertensive group, even after controlling for potentially confounding factors. Recently, Mari et al.38 also described an increased rate of fetal demise in IUGR without PE. This may be explained by an earlier diagnosis and elective delivery in those IUGR cases with severe maternal symptoms.

This study has several limitations. First, although the fetuses were followed longitudinally, only data from the last ultrasound scan before delivery were analyzed. This precluded any assessment of the potential existence of a different temporal sequence of cardiac changes in isolated IUGR from that in IUGR with PE. We and others have previously reported that cardiac functional parameters in IUGR become abnormal from very early stages of fetal deterioration3, 4. Therefore, the existence of such longitudinal differences between IUGR with and without PE seems unlikely, although they cannot be excluded conclusively. Second, the study mostly included severe preterm IUGR. Again, although unlikely, the potential influence of PE in less severe forms of IUGR later in pregnancy cannot be excluded completely. Finally, it was impossible to compile a study group with a meaningful sample size of isolated preterm PE, defined by PE with normally grown fetuses together with normal UA and MCA Doppler evaluation. Identification of such cases at the gestational ages covered by this study proved to be a challenge, as in most instances PE is associated with some degree of IUGR and/or fetal Doppler deterioration.

In conclusion, IUGR fetuses with and without PE showed a similar degree of cardiovascular dysfunction. These results support the concept that PE per se is not causally related to the presence of cardiovascular dysfunction in IUGR fetuses.

Acknowledgements

This study was supported by grants from the Fondo de Investigación Sanitaria (PI/060347 and PI/0690152) (Spain), Cerebra Foundation for the Brain Injured Child (Carmarthen, UK) and Thrasher Research Fund (Salt Lake City, UT, USA). F.C. is supported by a grant from the Carlos III Institute of Health (CM07/00076) (Spain).

Ancillary