Doppler changes in the main fetal brain arteries at different stages of hemodynamic adaptation in severe intrauterine growth restriction

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1 Ultrasound Obstet Gynecol 2007; 30: Published online 30 July 2007 in Wiley InterScience ( DOI: /uog.4084 Doppler changes in the main fetal brain arteries at different stages of hemodynamic adaptation in severe intrauterine growth restriction H. FIGUEROA-DIESEL*, E. HERNANDEZ-ANDRADE*, R. ACOSTA-ROJAS*, L. CABERO* and E. GRATACOS* *Fetal Medicine Unit, Department of Obstetrics and Gynecology, Vall D Hebron University Hospital, Universitat Autònoma de Barcelona and Department of Obstetrics, ICGON, Hospital Clínic and Fetal and Perinatal Medicine Group, IDIBAPS, University of Barcelona, Spain KEYWORDS: Doppler; fetal brain arteries; intrauterine growth restriction; redistribution ABSTRACT Objective To evaluate changes in the temporal evolution and regional distribution of arterial brain Doppler parameters in relation to different stages of hemodynamic adaptation in fetuses with severe intrauterine growth restriction (IUGR). Methods Thirty-six fetuses with severe IUGR ( 32 weeks of gestation) and abnormal umbilical artery (UA) pulsatility index (PI) (mean > 2 SD) were evaluated longitudinally with pulsed Doppler ultrasound at four different hemodynamic stages: Stage 1, mean UA-PI > 2 SD or absent UA end-diastolic flow; Stage 2 (n = 34), abnormal middle cerebral artery (MCA) PI (mean < 2SD);Stage3(n = 30), reversed UA enddiastolic flow; Stage 4 (n = 12), absent or reversed atrial flow in the ductus venosus. In addition, 36 normally grown fetuses were studied for comparison. PI and timeaveraged maximum velocity (TAMXV) in the MCA and the anterior cerebral (ACA), pericallosal (PER) and posterior cerebral (PCA) arteries were measured. Results In IUGR fetuses, PI values from all arteries were significantly reduced at Stage 2. At Stages 3 and 4, ACA-PI and PCA-PI did not change further, whereas MCA-PI and PER-PI showed a slight increase. In the ACA, MCA and PER, TAMXV in Stage 2 increased significantly. In Stages 3 and 4, ACA and PER-TAMXV remained unchanged, whereas MCA-TAMXV showed a slight decrease, mirroring the PI values. PCA-TAMXV values were similar to controls at all stages. Conclusion In IUGR fetuses, the brain arteries differ in the magnitude and time sequence of Doppler parameters in relation to systemic hemodynamic adaptation, suggesting the existence of regional brain redistribution processes. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Intrauterine growth restriction (IUGR) associated with placental insufficiency and chronic hypoxia complicates nearly 3 4% of all pregnancies 1. Up to 15% of all IUGR fetuses develop some degree of overt neurological damage, expressed mainly as hypoxic ischemic encephalopathy, leukomalacia, and/or cerebral palsy 2. However, as more data become available, a wider spectrum of subtle brain developmental disturbances has been described, including neuromuscular disorders, learning disabilities and behavioral misconduct 3 5. Our understanding of the adaptive processes occurring in the human fetal brain during growth restriction and our ability to predict subsequent neurological morbidity are still poor, with 50 60% of fetuses with abnormal blood flow in the umbilical artery (UA) showing suboptimal neurodevelopment during childhood 6. IUGR due to placental insufficiency is associated with chronic hypoxia, which in turn triggers a blood flow centralization process in order to maximize blood supply to key organs such as the brain, heart and adrenals. The temporal evolution of these changes during the process of deterioration within the fetal brain and the potential existence of regional variation have not, to our knowledge, been explored. In clinical practice, the centralization process is identified by a reduction in the pulsatility index (PI) in the middle cerebral artery (MCA) 7. Whether similar changes occur in all cerebral arteries and their relationship to fetal hemodynamic adaptation to severe IUGR remain Correspondence to: Dr E. Hernandez-Andrade, Equip de Recerca en Medicina i Terapia Fetal, Hospital Clìnic, Universidad de Barcelona, Sabino de Arana 1, Edificio Helios 2, Barcelona, Spain ( EHERNANDEZ@clinic.ub.es; powerdoppler@hotmail.com) Both authors contributed equally to this paper. Accepted: 22 February 2007 Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 298 Figueroa-Diesel et al. unknown. In animal models under hypoxia, the blood supply to different brain areas may differ substantially, and these regional differences are likely to be influenced greatly by gestational age and the type and severity of the insult Regional hemodynamic redistribution could be one of the mechanisms behind the existence of a regional hierarchy in brain deterioration, whereby certain areas are more susceptible than others to hypoxic damage. A few studies in IUGR fetuses have shown that the fetal brain arteries differ in their Doppler parameters, thus supporting the concept that the human fetal brain might experience hemodynamic internal variations during hypoxic IUGR 9,12,13. However, the influence of the stage of fetal deterioration with respect to these regional variations has not yet been studied. The purpose of this study was to evaluate the temporal sequence in arterial brain blood flow Doppler parameters in fetuses affected by severe IUGR at different stages of hemodynamic deterioration, and the potential differences in blood supply to different brain territories. METHODS Thirty-six singleton fetuses referred to our center for clinical management for severe IUGR, defined as a gestational age at diagnosis of 32 weeks, estimated fetal growth < 10 th percentile 14 and abnormal UA pulsatility index (PI) (> 2 SD) were studied longitudinally at intervals of between 1 and 4 days until delivery. The median maternal age at the time of diagnosis was 31 (range, 22 39) years and the median gestational age at enrolment was (range, to32+ 0) weeks. All of these fetuses underwent an evolution of hemodynamic changes that was classified into stages as follows: Stage 1, mean UA-PI > 2 SD or absent UA end-diastolic flow, and mean MCA-PI ± 2 SD; Stage 2 (n = 34), UA-PI > 2SDor absent UA end-diastolic flow, and mean MCA-PI < 2 SD; Stage 3 (n = 30), reversed UA end-diastolic blood flow and mean MCA-PI < 2 SD, with ductus venosus (DV) atrial flow present; Stage 4 (n = 12), reversed or absent atrial flow in the DV. This classification was based on the sequence of progressive hemodynamic changes in IUGR fetuses, expressed as a continuous increment in placental resistance (abnormal blood flow in the UA), a blood flow redistribution process (mean MCA-PI < 2 SD), a further increment in the peripheral resistance (reversed flow in the UA and abnormal flow in the venous system (increased PI), and signs of cardiac failure (reversed atrial flow in the DV and/or pulsations in the umbilical vein) 15. All cases entered the study at hemodynamic Stage 1 and only the first examination at each stage was recorded for the purposes of this study. The criteria for defining Stage 2 (MCA-PI < 2 SD) was based on only one of the vessels investigated for two reasons: first, MCA-PI < 2SD is one of the recognized stages of hemodynamic change in IUGR 15 and, second, we wanted to explore the behavior of the other brain arteries mainly when the MCA-PI value was within the normal range, so that there were no signs of blood flow centralization. Indications for delivery differed at different gestational ages: before 28 weeks, delivery was indicated by absent or reversed atrial flow in the DV (n = 8, four women decided to deliver and four decided to continue the pregnancy despite the poor prognosis); between 28 and 32 weeks, it was indicated by reversed end-diastolic flow in the UA or persistently abnormal fetal heart rate traces and/or altered biophysical profile (n = 24); after 32 weeks it was indicated by persistently abnormal MCA-PI (< 2SD) and abnormal flow in the UA or persistently abnormal fetal heart rate traces and/or altered biophysical profile (n = 4). Thus, the number of fetuses delivered at each stage of hemodynamic deterioration varied. In addition, 36 normally grown fetuses at a median gestational age of (range, to32+ 0) weeks were evaluated as controls. None of the IUGR or control fetuses had chromosomal or structural abnormalities. This project was approved by the institutional ethics committee and informed written consent to participate was obtained in all cases. Ultrasound and Doppler examinations were performed using a Siemens/Antares ultrasound machine (Siemens Medical Systems, Malvern, PA, USA) with a 6 2-MHz curved linear array. All Doppler examinations were performed in the absence of fetal corporal and respiratory movements and with the mother in voluntary suspended respiration. For the Doppler measurements, the angle of insonation was maintained below 30 and corrected manually when necessary. Directional color Doppler was used to clearly locate each vessel and a minimum of five consecutive regular waveforms was used for automatic calculation of PI and velocities. The mechanical and thermal indices were kept below 1. The mean examination time was 8 (range, 3 15) min. Pulsed Doppler examination of the UA-PI was performed in a free loop of the umbilical cord, and that of the DV was performed at its emergence from the portal vein, in a transverse or sagittal view of the fetal abdomen. The fetal brain arterial circulation was studied as follows. The MCA was examined immediately after its origin from the circle of Willis, in a transverse view of the fetal head. The anterior cerebral (ACA) and pericallosal (PER) arteries were both located in a transverse plane with a frontal projection of the fetal head, with the PER being located cranial to the ACA; the vessels showed opposite color Doppler patterns. In this projection the insonation angle was 0. The posterior cerebral artery (PCA) was studied in a transverse plane with a posterior projection and a clear view of the cerebellum (Figure 1). PI and timeaveraged maximum velocity (TAMXV) were recorded in all arteries. TAMXV was analyzed because it represents the movement of the blood cells traveling in the center of the vessel during the complete cardiac cycle and, therefore, can indicate indirectly the blood volume. Special care was taken to avoid unnecessary pressure in the fetal head as the blood flow velocities could be greatly affected. All Doppler studies were performed by one of two operators (H.F.D., E.H.A.). Intra- and Interclass correlation coefficients were estimated in 20 normal cases in the ACA.

3 Fetal brain circulation and growth restriction 299 Figure 1 Location and Doppler waveforms of the four arteries studied: (a) anterior cerebral artery, (b) pericallosal artery, (c) middle cerebral artery and (d) posterior cerebral artery. The anterior cerebral and pericallosal arteries are measured in the same anatomical projection, with the pericallosal artery being located cranial to the anterior cerebral artery. Only the results of the MCA, DV and UA Doppler examinations were made available to the clinicians. The decision to deliver the fetus was taken at the discretion of the managing physicians on the basis of current clinical protocols, as defined above. Data were stored in databases and analyzed with the SPSS 12.0 Statistical Package (SPSS Inc., Chicago, IL, USA). Comparisons between IUGR and normal fetuses were tested with the Wilcoxon Mann Whitney test. Differences within the IUGR hypoxic stages were estimated with the Kruskal Wallis test and, if present, they were confirmed with the Wilcoxon Mann Whitney test. RESULTS The survival rate in the IUGR group was 86% (31/36); there were two fetal and three neonatal deaths. The two stillbirths showed reversed atrial flow in the DV before 28 weeks and, despite detailed counseling, the parents decided not to deliver the fetus. The clinical characteristics of the study groups at delivery are summarized in Table 1. Doppler signals from all studied vessels were recorded in all cases. The intra- and interclass correlation coefficients were 0.92 (95% CI, ) and 0.86 (95% CI, ), respectively. Table 2 shows the PI values at the four different hemodynamic stages. Overall, IUGR fetuses showed a significant reduction in the PI values of all cerebral arteries as compared with controls. However, different patterns were observed in each vessel in relation to the hemodynamic adaptation. The ACAand MCA-PI values were significantly lower than those in controls at Stage 1 and decreased further (P = 0.001) at Stage 2. ACA-PI values remained the same at Stages 3 and 4 but MCA-PI values increased at Stages 3 and 4(P = 0.001). PER-PI in Stage 1 IUGR fetuses was not significantly different from that in controls, but there

4 300 Figueroa-Diesel et al. Table 1 Clinical characteristics of the study groups Characteristic IUGR group (n = 34) Control group Gestational age at delivery (weeks, median (range)) ( to ) ( to ) Birth weight (g, mean (range)) 985 ( ) 3217 ( ) 1-min Apgar score (median (range)) 7 (1 9) 9 (7 10) 5-min Apgar score (median (range)) 9 (4 10) 10 (8 10) Umbilical vein ph (mean (range)) 7.23 ( ) 7.26 ( ) Days in the NICU (n, median (range)) 36 (19 75) IUGR, intrauterine growth restriction; NICU, neonatal intensive care unit. Table 2 Pulsatility indices (PI) in the fetal brain arteries at different stages of hemodynamic adaptation to intrauterine growth restriction (IUGR) IUGR group Artery Control group Stage 1 Stage 2 (n = 34) Stage 3 (n = 30) Stage 4 (n = 12) Anterior cerebral 1.74 (0.34) 1.37 (0.32)* 1.15 (0.16)* 1.17 (0.21)* 1.14 (0.31)* Middle cerebral 2.01 (0.28) 1.75 (0.45)* 1.32 (0.22)* 1.56 (0.22)* 1.65 (0.24)* Posterior cerebral 1.63 (0.33) 1.16 (0.17)* 1.17 (0.16)* 1.15 (0.17)* 1.16 (0.32)* Pericallosal 1.54 (0.23) 1.48 (0.19) 1.12 (0.25)* 1.38 (0.22) 1.48 (0.28) Values are mean (SD). *P < 0.05 as compared with controls. Stage 1, mean umbilical artery (UA) PI > 2 SD or absent UA end-diastolic flow; Stage 2, mean middle cerebral artery PI < 2 SD; Stage 3, reversed UA end-diastolic flow; Stage 4, absent or reversed atrial flow in the ductus venosus. was a marked reduction at Stage 2 (P = 0.001) and a significant increment at Stages 3 and 4 (P = 0.001). In contrast, the PCA-PI showed a marked reduction at Stage 1 compared with controls, but no significant variations at the remaining stages (Figure 2a). In general, TAMXV values showed a mirror-like response with respect to PI values, apart from in the PCA (Table 3). In Stage 1, all vessels had small and non-significant differences in TAMXV with respect to controls. In Stage 2, TAMXV values increased significantly by 43 61% in the ACA, MCA and PER, whereas the PCA exhibited a modest (18%) non-significant increment in TAMXV. In Stages 3 and 4, TAMXV in the ACA and PER remained unchanged, whereas in the MCA it showed a slight reduction (Figure 2b). DISCUSSION We found different temporal changes in the fetal cerebral arteries in relation to the systemic hemodynamic changes occurring in cases with severe IUGR. In terms of the PI, the ACA and the PCA seemed to respond earlier, with a significant reduction in Stage I. In terms of velocity, TAMXV showed a mirror-like behavior with respect to pulsatility in the ACA, MCA and PER, suggesting that the reduction in the PI in these vessels was probably associated with increments in blood supply. However, this increase in TAMXV was not observed in the PCA, in spite of a profound reduction in PI values. This may suggest the existence of redistribution processes, whereby some brain territories might fail to increase blood supply as effectively as do others. There are few reports addressing the simultaneous investigation of the main fetal cerebral arteries. In normal pregnancies, Hata et al. 16 reported a reduction in the resistance index of the ACA, MCA and PCA from 28 weeks onwards. In IUGR fetuses, van den Wijngaard et al. 17 showed a constantly reduced PCA- PI value (mean < 2 SD) as compared with MCA-PI and ACA-PI. Conversely, Noordam et al. 18 found that MCA showed the most pronounced changes in PI in IUGR fetuses, and recently Dubiel et al. 19, in a group of high-risk pregnancies, described that ACA-PI showed the highest association with an adverse perinatal outcome. All these studies agree with the notion of a general reduction in cerebral vascular resistance, but differ with respect to which vessel is most affected. A poor, case-specific definition of IUGR, lack of longitudinal evaluation and differences in severity of IUGR and gestational age at enrolment could explain such differences. Our findings areinlinewiththoseofdubielet al. 19, who described the ACA as the artery showing the earliest changes in IUGR. We also found that the PCA likewise presented an earlier response. This conclusion is based on the observation that, despite all fetuses having a normal MCA-PI value in hemodynamic Stage 1, some of them at this stage showed significantly reduced ACA-PI and PCA-PI values as compared with controls. Another finding of our study was that from Stage 2 onwards, PI values did not decrease. It is possible that the fetal brain reaches the maximum vascular vasodilation response by Stage 2, as defined in this study. In the presence of more severe hemodynamic changes (reversed UA end-diastolic flow and absent or reversed atrial flow in the DV), PI values from the MCA and PER even tended

5 Fetal brain circulation and growth restriction 301 (a) Pulsatility index (b) Stage: ACA MCA PCA PER TAMXV (cm/s) Stage: ACA MCA PCA PER Figure 2 Pulsatility index (a) and time-averaged maximum velocity (TAMXV) (b) in the four brain arteries studied at different stages of hemodynamic adaptation in intrauterine growth-restricted (, IUGR) fetuses and controls ( ). Stage 1, mean umbilical artery (UA) PI > 2 SD or absent UA end-diastolic flow; Stage 2 (n = 34) mean middle cerebral artery PI < 2 SD; Stage 3 (n = 30), reversed UA end-diastolic flow; Stage 4 (n = 12), absent or reversed atrial flow in the ductus venosus. * P < 0.05 as compared with controls. ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PER, pericallosal artery. Table 3 Time-averaged maximum velocity (in cm/s) in the fetal brain arteries at different stages of hemodynamic adaptation to intrauterine growth restriction (IUGR) IUGR group Artery Control group Stage 1 Stage 2 (n = 34) Stage 3 (n = 30) Stage 4 (n = 12) Anterior cerebral 13.8 (4.0) 15.2 (5.0) 21.5 (5.0)* 22.3 (5.2)* 21.8 (5.1)* Middle cerebral 18.3 (4.3) 20.8 (6.1) 26.2 (4.7)* 25.2 (4.2)* 25.1 (6.0)* Posterior cerebral 14.8 (6.0) 16.6 (4.2) 17.7 (3.7) 17.3 (4.1) 16.8 (4.7) Pericallosal 10.1 (4.8) 11.2 (3.9) 15.3 (4.7)* 16.8 (3.2)* 16.4 (3.5)* Values are mean (SD). *P < 0.05 as compared with controls. Stage 1, mean umbilical artery (UA) PI > 2 SD or absent UA end-diastolic flow; Stage 2, mean middle cerebral artery PI < 2 SD; Stage 3, reversed UA end-diastolic flow; Stage 4, absent or reversed atrial flow in the ductus venosus. to increase. This finding has been reported previously by Konje et al. 20, who described an increment in MCA-PI, or reversal adaptation, in severely affected IUGR fetuses. They also described a reduction in the MCA volume blood flow prior to the increment in MCA-PI. The mirror-like pattern observed between MCA-TAMXV and MCA-PI at hemodynamic Stages 3 and 4 is in accordance with this observation. Furthermore, we observed a similar pattern in the PER. This study had several potential limitations. The evaluated parameters are only indirect estimates of true blood perfusion. As illustrated in this study, changes in pulsatility may not necessarily imply true changes in organ blood perfusion. Although also an indirect estimate of cerebral perfusion, the second parameter used in this study, TAMXV, may provide more relevant information on blood supply 21,22. Another potential limitation is that the evaluated arteries provide blood

6 302 Figueroa-Diesel et al. supply to ill-defined anatomical areas with a marked component of vascular shunting, and so the data should not be used to infer which territories are specifically involved in the observed changes. The use of recently described techniques to evaluate tissue perfusion might allow more detailed exploration of changes in specific regions 23 ; such studies are now underway. Finally, our definition of the progression of fetal hemodynamic adaptation was based on experimental and clinical reports, in which a continuous insult, probably hypoxia, produces an increment in the peripheral tissue resistance followed by a sequence of fetal cardiovascular protective mechanisms While we cannot exclude some degree of overlapping between clinical cases, we believe that the classification used identified fetuses at different stages of hemodynamic adaptation. To our knowledge, this is the first longitudinal and simultaneous study of the three major fetal brain arteries, and the first addressing the PER in the hypoxic fetus. Analysis of these vessels contributes important information on the adaptive hemodynamic brain changes and the progression of fetal deterioration occurring in the presence of chronic fetal hypoxia. The data support the notion that hemodynamic brain changes could be used to understand the sequence of processes leading to irreversible neurological damage. ACKNOWLEDGMENTS This project was carried out thanks to the support of Cerebra, Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and Thrasher Research Fund (Salt Lake City, USA). H.F.D. was supported by research fellowships of the Universidad de los Andes in Chile and Cerebra. 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