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Keywords:

  • brain injury;
  • cardiac defects;
  • fetus;
  • hypoplastic left heart;
  • middle cerebral artery Doppler;
  • prenatal diagnosis;
  • transposition of the great arteries

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objectives

To assess changes in the Doppler flow profiles of the middle cerebral artery in fetuses with cardiac defects theoretically associated with impaired cerebral oxygen delivery in utero.

Methods

Z-scores were calculated for pulsatility and resistance indices (PI and RI, respectively) of the middle cerebral artery (MCA) and the cerebroplacental ratio (CPR) between 19 and 41 weeks' gestation, and for head circumference at birth (HC), in 113 fetuses with the following isolated cardiac defects: transposition of the great arteries (TGA; n = 18), hypoplastic left heart (HLH; n = 46), severe aortic stenosis (n = 17), pulmonary atresia (n = 18) and tetralogy of Fallot (TOF; n = 14). Pregnancies with uteroplacental dysfunction (indicated by increased uterine and/or umbilical Doppler indices), growth restriction, extracardiac malformations, chromosomal anomalies as well as multiple pregnancies were excluded to avoid any additional hypoxemic effect as strictly as possible. The results were compared with 1378 normal controls.

Results

Fetuses with pulmonary atresia, severe aortic stenosis and TOF had no significant alterations of Doppler parameters or HC at birth. In fetuses with TGA, mean Z-scores of HC at birth were significantly smaller compared with controls (mean ± SD, −0.73 ± 1.25; P < 0.05), but there was no significant difference in the Doppler parameters. Fetuses with HLH had significantly lower MCA-PI (−0.57 ± 0.74; P < 0.05), MCA-RI (−0.73 ± 0.85; P < 0.05), CPR (−1.44 ± 1.05; P < 0.05) and HC (−0.50 ± 1.24; P < 0.05) Z-scores compared with controls.

Conclusions

Fetuses with cardiac defects theoretically associated with markedly impaired cerebral oxygen delivery in utero (TGA and HLH) have smaller HCs at birth. However, only fetuses with HLH have cerebrovascular alterations that are detectable by evaluation of the Doppler indices MCA-PI, MCA-RI and CPR. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Several studies have shown that many children with congenital heart disease survive with motor, verbal, non-verbal (visuospatial), behavioral, social and academic problems that impair their progress in school1, 2. Although these disabilities have often been attributed to brain injury from surgery or support procedures, such as hypothermic circulatory arrest and cardiopulmonary bypass, or from postoperative complications, such as cardiac arrest, infection or poor cerebral perfusion, a substantial percentage of children are found to have cognitive impairments regardless of the type of cardiopulmonary bypass treatment3, 4. Indeed, more than half of newborns with congenital heart disease have neurological abnormalities before surgery5 resulting from chromosomal or genetic abnormalities, brain dysgenesis in concert with congenital heart defect and/or acquired hypoxic–ischemic brain injury (e.g. due to ongoing hemodynamic instability), most likely to have occurred in utero4–7. Accordingly, the Washington–Baltimore study found increased rates of microcephaly at birth in selected categories of isolated congenital heart disease8. These results were confirmed by a number of studies7, 9–11, but not by others12.

A possible explanation for these findings could be an intrauterine hypoxemia-induced brain injury caused by the altered hemodynamics of the cardiac defect itself. A marked decrease in the oxygen saturation of cerebral blood could be hypothesized in transposition of the great arteries (TGA) (direct delivery of deoxygenated blood), hypoplastic left heart (HLH) (retrograde flow of deoxygenated blood from the right heart across the aortic isthmus), pulmonary atresia and, to a lesser degree, tetralogy of Fallot (TOF) (cardiac mixing of oxygenated and deoxygenated blood)10.

Fetuses with decreased oxygen delivery due to placental dysfunction display cerebral vasodilatation enhancing cerebral perfusion as an adaptive phenomenon13. This ‘brain-sparing’ effect can be quantified using spectral Doppler imaging of the middle cerebral arteries (MCA), which reveals a marked decrease in pulsatility.

In recent years, a number of studies have addressed the question of whether there is a comparable brain-sparing effect in fetuses with cardiac defects theoretically associated with impaired cerebral oxygen delivery10, 14–16, with conflicting results. Most authors could demonstrate a reduced pulsatility in the MCA of fetuses with TGA but the results varied when other cardiac defects were taken into account. In our own previous study, we were unable to demonstrate a significant effect in 55 fetuses with diverse isolated cardiac defects17.

However, in most of the previous studies, the subgroups of fetuses with singular cardiac defects were small and additional factors possibly resulting in fetal hypoxemia, such as uteroplacental dysfunction, fetal growth restriction, malformation syndromes, multiple pregnancies and chromosomal defects, were not unequivocally excluded. These potential biases might explain the differing results. We therefore retrospectively reviewed all fetuses with isolated cardiac defects associated with reduced oxygen delivery to the brain seen over a period of 10 years, excluding additional factors as far as possible and evaluating the results in different periods of gestation.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The study population comprised the fetuses of pregnant women referred for fetal echocardiography in two tertiary referral centers (Lübeck 1998–2002 and Bonn 2003–2008).

In the study period, all patients with the following isolated cardiac lesions were identified in our fetal database: TGA (atrioventricular concordance and ventriculoarterial discordance), pulmonary atresia (with ventricular septal defect or intact ventricular septum), TOF, HLH (aortic atresia with HLH or mitral atresia in combination with aortic atresia and virtual absence of left ventricular cavity) and severe aortic stenosis with reversal of flow in the aortic arch. Uneventful pregnancies with normal fetal anatomy and known outcome from our database were used as controls.

The following cases were excluded: gestational age < 19 weeks or > 41 weeks; small-for-gestational age (birth weight < 10th centile)18; extracardiac malformations; chromosomal abnormalities; persistent non-sinus rhythm; maternal conditions that might affect fetal hemodynamics, such as gestational diabetes, thyroid disease or pre-eclampsia; multiple gestations; and bilateral notching in the uterine arteries or mean pulsatility index (PI) > 95th centile after 23 weeks' gestation.

In each fetus, the following measurements were taken into account: MCA-PI and MCA resistance index (RI) from 19 weeks onward, cerebroplacental ratio (CPR) from 21 weeks onward and head circumference (HC) on the day of birth. Doppler recordings were obtained from the proximal third of the MCA during fetal apnea and a fetal heart rate of 120–160 beats per min. PI and RI were calculated for all measurements by means of the following formulae: PI = (S − D)/TAMX and RI = (S − D)/S, where S is the systolic peak velocity (maximum velocity), D is the end-diastolic velocity and TAMX is the time-averaged maximum velocity across cardiac cycles19.

CPR quantifies the redistribution of cardiac output by dividing Doppler indices from the umbilical artery (UA) and the MCA. In our study, the CPR was derived as a ratio of the MCA-PI divided by the UA-PI20–22.

If multiple measurements were available in one patient, only the measurement closest to term was included. In order to make comparisons independent of gestational age, the measurements were converted into Z-scores using published normative data from large populations of healthy fetuses. For the calculation of Z-scores of MCA-PI, MCA-RI, CPR and HC, normative data from Ebbing et al.22 and Voigt et al.18 were used.

Continuous variables are expressed as mean ± SD. Doppler indices were compared between diagnostic groups using one-way ANOVA with post-hoc Bonferroni testing and Student's t-test to determine differences between two groups. Dichotomous variables were analyzed using chi-square and Fisher's exact test. P < 0.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In the study period, 113 fetuses with cardiac defects and 1378 healthy fetuses met the inclusion criteria. Among the cases with cardiac defects 18 had TGA, 18 had pulmonary atresia (nine with a ventricular septal defect and nine with an intact ventricular septum), 14 had TOF, 46 had HLH, and 17 had severe aortic stenosis with reversal of flow in the aortic arch and the ascending aorta.

From the 113 cases with cardiac defects, 19 pregnancies were terminated, four fetuses died in utero, 78 were liveborn and 12 were lost to follow-up. At least one measurement was available in 113 patients for MCA-PI and MCA-RI, in 105 patients for CPR and in 72 patients for HC at birth. These results are summarized in Table 1.

Table 1. Z-scores and fraction of values < −2 SD for middle cerebral artery (MCA) pulsatility index (PI) and resistance index (RI), cerebroplacental ratio (CPR) and head circumference (HC) at birth, for fetuses with isolated heart defects in comparison to controls
GroupMCA-PIMCA-RICPRHC
Mean ± SDn < −2 SDMean ± SDn < −2 SDMean ± SDn < −2 SDMean ± SDn < −2 SD
  • Analysis of Doppler parameters used the last measurement obtained for each fetus, between 19 and 41 weeks' gestation. CHD, congenital heart defects; HLH, hypoplastic left heart; PA, pulmonary atresia; SAS, severe aortic stenosis; TGA, transposition of the great arteries; TOF, tetralogy of Fallot.

  • *

    P < 0.05 vs. controls.

TGA−0.04 ± 0.660/18−0.08 ± 0.900/18−0.31 ± 1.070/17−0.73 ± 1.25*2/14*
HLH−0.57 ± 0.74*2/46*−0.73 ± 0.85*2/46−1.44 ± 1.05*10/43*−0.50 ± 1.24*3/26*
SAS−0.31 ± 0.590/17−0.65 ± 0.800/17−0.70 ± 1.262/14−0.82 ± 1.230/10
PA−0.18 ± 1.240/18−0.08 ± 1.040/18−0.85 ± 1.043/17−0.01 ± 1.291/14
TOF0.25 ± 0.740/140.07 ± 0.880/14−0.55 ± 1.442/140.10 ± 0.800/8
All CHD−0.28 ± 0.852/113−0.41 ± 0.932/113−0.94 ± 1.20*17/105−0.20 ± 1.28*6/72*
Controls−0.22 ± 0.816/1378−0.30 ± 0.8955/1378−0.66 ± 1.17158/12430.08 ± 1.0724/1327

Fetuses with pulmonary atresia, severe aortic stenosis and TOF had no significant alterations of mean MCA-PI, MCA-RI, CPR and HC at birth Z-scores. Accordingly, the proportion of values < −2 SD was not significantly different between fetuses with pulmonary atresia, severe aortic stenosis or TOF and controls (Figures 1 and 2).

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Figure 1. Middle cerebral artery (MCA) pulsatility index (PI) (a) and resistance index (RI) (b) in 113 fetuses, and cerebroplacental ratio (CPR) (c) in 105 fetuses with cardiac defects plotted against gestational age. Solid lines represent 5th and 95th percentiles of 1378 controls. •, Controls; □, hypoplastic left heart; ×, pulmonary atresia; +, severe aortic stenosis; ○, TGA, transposition of the great arteries; ▵, tetralogy of Fallot.

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thumbnail image

Figure 2. Z-scores of middle cerebral artery (MCA) pulsatility index (PI) (a) and resistance index (RI) (b) in 113 fetuses, cerebroplacental ratio (CPR) in 105 fetuses (c) and head circumference (HC) at birth in 72 fetuses (d) with cardiac defects. Horizontal bars show medians, boxes show upper and lower quartiles, whiskers show range and dots show outliers. Arrows denote P < 0.05 vs. controls. HLH, hypoplastic left heart; PA, pulmonary atresia; SAS, severe aortic stenosis; TGA, transposition of the great arteries; TOF, tetralogy of Fallot.

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In newborns with TGA, mean Z-scores of HC at birth were significantly smaller compared with controls (−0.73 ± 1.25; P < 0.05) (Figure 2) and the proportion of HC Z-scores < −2 SD was significantly higher (2/14 vs. 24/1327; P < 0.05), whereas there was no significant difference in Z-scores and the proportion of values < −2 SD for MCA-PI, MCA-RI and CPR (Figures 1 and 2).

Fetuses with HLH had significantly lower MCA-PI (−0.57 ± 0.74; P < 0.05), MCA-RI (−0.73 ± 0.85; P < 0.05), CPR (−1.44 ± 1.05; P < 0.05) and HC (−0.50 ± 1.24; P < 0.05) Z-scores compared with controls. Accordingly, the proportion of Z-scores < −2 SD was significantly higher for MCA-PI (2/46 vs. 6/1378; P < 0.05), CPR (10/43 vs. 158/1243; P < 0.05) and HC (3/26 vs. 24/1327; P < 0.05) (Figures 1 and 2).

Similar results were found when different periods during gestation were analyzed separately (19–25 weeks', 26–32 weeks' and 33–41 weeks' gestational age) (Figure 3). Significant differences in comparison to controls were only found for the MCA-PI and CPR Z-scores of HLH fetuses at 26–32 weeks.

thumbnail image

Figure 3. Z-scores of middle cerebral artery (MCA) pulsatility index (PI) (a) and resistance index (RI) (b) in 113 fetuses, and cerebroplacental ratio (CPR) in 105 fetuses (c) according to gestational age: 19–25 weeks □, 26–32 weeks equation image and 33–41 weeks (equation image). Horizontal bars show medians, boxes show upper and lower quartiles, whiskers show range and dots show outliers. Arrows denote P < 0.05 vs. controls. HLH, hypoplastic left heart; PA, pulmonary atresia; SAS, severe aortic stenosis; TGA, transposition of the great arteries; TOF, tetralogy of Fallot.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In the past decade, a number of prenatal Doppler studies have investigated whether fetuses with cardiac defects associated with relative cerebral hypoxemia display signs of cerebrovascular autoregulation, comparable to the ‘brain-sparing effect’ in growth-restricted fetuses. In an initial study from our group, we analyzed 115 fetuses with various cardiac defects and found no significant alterations in cerebral and placental flow velocities when cases of growth restriction, extracardiac anomalies and aneuploidies were excluded17. However, only 55 fetuses met the inclusion criteria and the number of single cardiac defects was too small to allow separate analyses. In subsequent years, this study was challenged by a number of authors.

Modena et al. analyzed 71 fetuses with various congenital heart defects and found significantly more values < 5th centile for MCA-PI Z-scores and CPR Z-scores in the affected fetuses than in gestational age-matched controls16. Donofrio et al. published a prospective study of 36 fetuses with sonographically diagnosed cardiac defects10. They used CPR as a measure of cerebral autoregulation, and found both decreased CPR and reduced HC measurements in a significant number of fetuses. Cases associated with single ventricle morphology had the strongest alterations of Doppler parameters, whereas the changes were less pronounced in aortic stenosis, TOF and TGA. However, owing to the small number of cases the study was underpowered for cases with transposition and hypoplastic right heart, and the results were not matched for gestational age. Similarly, Kaltman et al., who looked cross-sectionally at 58 fetuses with HLH, or with left- and right-sided obstructive lesions, found that fetuses with HLH had significantly reduced MCA-PI Z-scores, whereas they were unchanged in those with left- and right-sided obstructive lesions14. They found an increased UA impedance in the fetuses with obstructive lesions, significantly only for right-sided lesions. In CPR, however, no differences were found between their cohort and the control group. The HCs at birth were not assessed in that study.

In our present study, we could reproduce the reduced pulsatility in the MCA as well as the reduced CPR and the smaller HC in fetuses with HLH. As in previous studies, no changes could be demonstrated in cases with severe aortic stenosis, TOF and pulmonary atresia. In the latter two cardiac defects the decrease in cerebral oxygen content is less pronounced. However, the question arises why fetuses with HLH have decreased cerebrovascular impedance and smaller head sizes, whereas fetuses with severe aortic stenosis and reversal of flow in the aortic arch do not, given that the expected decrease in oxygen delivered to the brain is similar in both groups. Donofrio et al. proposed that the single ventricle may not be able to increase ventricular output sufficiently to compensate for the cerebral hypoxemia, despite decreased cerebral resistance10. The hypoplastic and reversely perfused aortic isthmus may additionally limit cerebral perfusion in these fetuses. Conversely, they hypothesized that in severe aortic stenosis a small proportion of well oxygenated blood will reach the brain even in the presence of a reversely perfused arch10. It is, however, dubious whether this small amount of antegrade flow improves the delivery of blood volume or oxygen content to the brain. In our cohort, the small sample size might also have influenced the results.

Intracardiac mixing of blood in the presence of two ventricles and unobstructed antegrade cerebral flow might enable the heart to compensate for cerebral hypoxemia by increasing combined ventricular output10. This might explain why our results showed unaltered Doppler parameters in fetuses with TGA, which are the most likely to have decreased oxygen content of cerebral blood. Conflictingly, Jouannic et al. found significantly lower mean MCA-PIs in 22 fetuses with TGA compared with controls15. The significantly reduced HCs in newborns with transposition in our present study and in those from the literature8 support the results of the Doppler studies of Jouannic et al.15 but additional factors seem to influence the cerebrovascular hemodynamics in these cases.

Given the inconsistent findings of the various studies that assessed the pattern of redistribution of cerebral blood flow and the frequency of microcephaly in fetuses and newborns with congenital heart defects, brain injury in newborns with cardiac defects is most probably multifactorial and cumulative during life, and not only a consequence of disordered fetal circulation9, 23. Furthermore, the relationship between fetal growth restriction and CHD appears to be complex. It has been postulated that growth abnormality as the primary insult could lead to alteration of cardiogenesis and subsequent disturbance in fetal hemodynamics leading to structural heart defect24, 25. This could explain the high frequency of growth disturbances in fetuses with congenital heart disease. Fetal growth restriction does not alone, however, explain the poor head growth in congenital heart disease. Numerous studies, including our own, controlled for body weight7, 8, 11 and still observed increased rates of microcephaly at birth. Barbu et al. demonstrated in a cohort of children with congenital heart disease that being born with a birth weight appropriate-for-gestational age reduces the risk of microcephaly by close to 80%7. In their study, children with HLH had normal HCs once the subgroup of children that was small-for-gestational age was excluded. Accordingly, in our cohort where fetuses with growth restriction and uteroplacental dysfunction were excluded from the start, children born with HLH had only slightly smaller HCs than controls, whereas the difference was more pronounced in newborns with TGA. Again, this suggests that additional factors other than impaired cerebral oxygen delivery play a role in the genesis of microcephaly in fetuses with HLH.

Furthermore, there is growing evidence that the proportion of fetuses with uteroplacental dysfunction and consecutive hypoxemia increases near to, at or after term. This is reflected by the increasing proportion of fetuses that are small-for-gestational age26, the increasing rate of stillbirths27, the development of a mixed respiratory and metabolic cord blood acidemia with advancing gestational age28, the decreased pulsatility in the Doppler velocity waveforms in the MCA22, and the increased proportion of retrograde flow in the aortic arch29. These findings are another possible explanation for the inconsistent Doppler findings in the MCA in fetuses with TGA in our study from which fetuses at risk for uteroplacental dysfunction were rigorously excluded.

Determining the risk to the developing fetal brain posed by coexistent congenital heart disease could profoundly affect clinical approaches to prenatal counseling, fetal biophysical monitoring, and obstetric management such as timing of delivery. However, given the inconsistent and sometimes conflicting results of this and previous studies, we are far from being able to make clinical recommendations.

In summary, our study showed that fetuses with cardiac defects potentially associated with markedly impaired cerebral oxygen delivery in utero (TGA and HLH) had smaller HCs at birth. However, only fetuses with hypoplastic left ventricle had cerebrovascular alterations detectable by the prenatal pulsed Doppler techniques and indices that were used. Therefore, additional factors are likely to influence the cerebrovascular autoregulation in these fetuses, which prevents us from drawing conclusions concerning their clinical management.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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