HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2383042213v1 238/3/872    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wedegärtner, U. Articles by Schröder, H. J. Search for Related Content PubMed PubMed Citation Articles by Wedegärtner, U. Articles by Schröder, H. J.

Functional MR Imaging: Comparison of BOLD Signal Intensity Changes in Fetal Organs with Fetal and Maternal Oxyhemoglobin Saturation during Hypoxia in Sheep¹

¹ From the Department of Diagnostic and Interventional Radiology (U.W., S.S., A.N.P., G.A.), Department of Obstetrics and Prenatal Medicine (M.T.), and Division of Experimental Gynecology, Department of Obstetrics and Prenatal Medicine (H.J.S.), University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany; and Philips Medical Systems, Hamburg, Germany (H.K.). Received December 30, 2004; revision requested February 16, 2005; revision received May 4; final version accepted June 13. Supported by Deutsche Forschungsgemeinschaft We 2826/1-1. Address correspondence to U.W. (e-mail: wedegaer{at}uke.uni-hamburg.de).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Purpose: To compare relative changes in blood oxygen level–dependent (BOLD) signal intensity in the fetal brain, liver, heart, lungs, and cotyledon with maternal and fetal blood oxygenation during maternal hypoxia in sheep.

Materials and Methods: All experimental protocols were reviewed and approved by local authorities on animal protection. Six anesthetized ewes carrying singleton fetuses underwent magnetic resonance (MR) imaging with rapid single-shot echo-planar imaging BOLD sequence. BOLD imaging of the fetal brain, lungs, liver, heart, and cotyledon was performed during a control phase (ie, normoxia) and a hypoxic phase. Maternal oxyhemoglobin saturation was recorded continuously with pulse oximetry. Fetal blood samples were obtained with a carotid catheter at each phase. Regions of interest were placed in fetal organs. Normalized BOLD signal intensity was calculated with mean values of control and hypoxic plateaus. BOLD signal intensity was correlated with maternal oxyhemoglobin saturation and fetal oxyhemoglobin saturation; linear regression analysis was performed.

Results: Control maternal and fetal oxyhemoglobin saturation values were 97% (95% confidence interval [CI]: 95%, 100%) and 62% (95% CI: 51%, 73%), respectively. During hypoxia, maternal and fetal oxyhemoglobin saturation values decreased to 75% (95% CI: 65%, 85%) and 23% (95% CI: 17%, 29%), respectively. Fetal BOLD signal intensity decreased to 81% (95% CI: 73%, 88%) in the cerebrum, 78% (95% CI: 67%, 89%) in the cerebellum, 83% (95% CI: 80%, 86%) in the lungs, 58% (95% CI: 33%, 84%) in the liver, 53% (95% CI: 43%, 64%) in the heart, and 71% (95% CI: 48%, 94%) in the cotyledon. Correlation of fetal BOLD signal intensity was stronger with fetal (r = 0.91) than with maternal (r = 0.68) oxyhemoglobin saturation; however, the difference was not significant. The highest slope values were obtained for the heart: 1.68% BOLD signal intensity increase per 1% maternal oxyhemoglobin saturation (95% CI: 1.58, 1.77) and 1.04% BOLD signal intensity increase per 1% fetal oxyhemoglobin saturation (95% CI: 0.94, 1.13).

Conclusion: BOLD MR imaging can be used to measure changes of oxyhemoglobin saturation in fetal organs during hypoxia. The liver and heart demonstrated the greatest signal intensity decreases during hypoxia.

© RSNA, 2006

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
The effect of human fetal magnetic resonance (MR) imaging on the evaluation of fetal anomalies has been demonstrated in several studies (1–5). In addition to anatomic and morphologic information, MR imaging also provides an opportunity to perform functional imaging. Functional MR techniques—such as blood oxygen level–dependent (BOLD) contrast, perfusion- and diffusion-weighted sequences, and MR spectroscopy—deliver information about blood oxygenation, blood flow, diffusion properties, and concentration changes of specific substances—such as lactate and adenosine triphosphate in tissues. So far, functional BOLD MR imaging has been used mainly to investigate brain activation (6–9). It has been proved that functional MR imaging is capable of demonstrating changes in fetal blood oxygenation during hypoxia (10). Thus, BOLD MR imaging may be a useful tool in the noninvasive measurement of the state of blood oxygenation in the fetus; this is of clinical importance in detecting and monitoring an at-risk fetus (eg, growth-restricted fetus).

The purpose of this study was to evaluate changes in the fetal BOLD signal intensity of the brain, lungs, heart, liver, and cotyledon and the relationship between maternal and fetal oxyhemoglobin saturation during maternal hypoxia in sheep.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
All experimental protocols were reviewed and approved by the local authorities on animal protection.

Animals and Instrumentation
MR imaging was performed in six ewes carrying singleton fetuses at gestational ages of 117–125 days (full gestation term, 145 days). All fetuses were examined with a carotid catheter and a cerebral probe during general anesthesia, as follows: A short catheter was inserted into an external jugular vein of the ewe. The ewes were sedated with xylazine (Rompun; Bayer-Vital, Leverkusen, Germany) (0.25 mg per kilogram of body weight), intubated after intravenous administration of a total of 1 g of barbiturate (Trapanal; Altana Pharma, Konstanz, Germany), and anesthetized by means of artificial ventilation with 1% isoflurane (Forene; Abbot, Wiesbaden, Germany) with a 2:1 mixture of oxygen and nitrous oxide (oxygen, 2 L/min; nitrous oxide, 1 L/min). The fetus was approached with laparotomy and hysterotomy, and the fetal head was exteriorized. A scalp incision was made, and a 1.5-mm-diameter hole was drilled into the left parietal bone. For measurement of partial pressure of oxygen in the brain, a probe was inserted into the left fetal hemisphere and fixed to the skull with dental cement and tissue glue; however, these measurements are not included in this report. A catheter was inserted into the right carotid artery to obtain fetal blood samples. The fetal and maternal incisions were closed. The catheter and probe were exteriorized to the ewe's left flank and stored in a pouch attached to the maternal skin (M.T., H.J.S.).

MR Settings and Imaging
Animal preparation.—Between 4 and 7 days after surgery, the ewes were sedated with 20 mg diazepam (Ratiopharm, Ulm, Germany) and 250 mg ketamine (Parke-Davis, Karlsruhe, Germany) administered intravenously in the external jugular vein and repeated as required. The ewes were then intubated and transferred from the animal care facility to the MR imaging unit. During MR imaging, the ewes were artificially ventilated (1%–2% isoflurane in oxygen/nitrous oxide; tidal volume, 600–1000 mL; six to 11 cycles per minute). Maternal oxyhemoglobin saturation was monitored with a pulse oximeter system (Nonin Medical, Plymouth, Minn). The sensor was attached to the maternal tongue and connected with the system via a 9-m fiberoptic cable. The pulse oximetry data were stored (sampling rate, 0.39 per second) on a personal computer with a data acquisition system (WP 100; Biopac Systems, Santa Barbara, Calif). At the beginning of each experiment, the MR system and personal computer were synchronized. The respirator, data acquisition system, and pulse oximeter were situated outside the MR imaging room. The ewe was connected to the respirator with rigid pipes (total length, 8 m) and standard anesthesia hoses that were assembled for the experiments. All animals were examined in a lateral position.

MR imaging.—MR imaging was performed once in each animal with a 3.0-T MR imager (Intera; Philips Medical Systems, Best, the Netherlands) with a six-element phased-array cardiac coil for signal reception. Initially, T2-weighted fast spin-echo sequences (repetition time msec/echo time msec, 4454/120; matrix, 294 x 256) were performed in the fetuses to enable general orientation. One or two stacks of sections—including the fetal brain, heart, lungs, and liver—were manipulated with the aim of examining the fetus in the transverse orientation. For BOLD imaging, T2^*-weighted single-shot gradient-echo echo-planar sequences were used (field of view, 180 mm; acquired resolution, 2.25 x 2.25 mm; reconstructed resolution, 1.4 x 1.4 mm; acquired matrix, 80 x 80; reconstructed matrix, 128 x 128; section thickness, 5 mm; intersection gap, 1 mm; flip angle, 90°). For sequence optimization, an echo time of 45 msec was used in the first two animals examined, and an echo time of 30 msec was used in the subsequent four animals. Saturation bands were used to minimize fold-over artifacts in the phase-encode direction. Imaging was triggered by ventilation. In each examination, 250–300 consecutive BOLD measurements with one or two stacks of seven to 13 sections were acquired at intervals of 8–16 seconds (the interval depended on the maternal ventilation rate) for a total sampling time of 30–40 minutes. In accordance with the repetition time of 8 seconds, BOLD measurements were performed every 8 seconds if the duration of respiration was within 8 seconds.

Hypoxia protocol.—Each experiment consisted of a control period and one level of hypoxia (duration of each plateau, 5–10 minutes). BOLD MR images were acquired with no interruption. During the control period, maternal oxyhemoglobin saturation of 90%–100% was desired. For hypoxia, oxygen was reduced in the ventilated gas mixture and adjusted, as necessary, to keep maternal oxyhemoglobin saturation at a constant level of approximately 60%–80%. When stable fetal BOLD signal intensities were reached, imaging continued for another 5–10 minutes. Arterial blood samples from the fetuses were obtained during the control and hypoxic periods. Fetal arterial oxyhemoglobin saturation was measured with a blood gas analyzer (ABL 700; Radiometer, Copenhagen, Denmark).

Normalization of BOLD signal intensity.—BOLD signal intensity during hypoxia (BOLD SI) was expressed as a percentage of the mean control values and calculated by using the following equation: BOLD SI = SI_hypoxia/SI_control x 100, where SI_control is signal intensity during the control phase and SI_hypoxia is signal intensity during the hypoxic phase. For normalization purposes, the following procedure was used: The initial control phase and subsequent steady-state hypoxic phase were identified on the scatterplot. Temporal mean values of the phases were derived (BOLD signal intensities of the respective region of interest [ROI] and maternal oxyhemoglobin saturation). During the control and hypoxic phases, signal intensity was approximately constant within a plateau. Thus, there should not be a large effect of averaging variation. On average, 31 MR images were needed for averaging in either the control phase or the hypoxic phase (range, 27–36 MR images), which is equivalent to time periods of 4–8 minutes.

ROI Measurement
General ROI measurements.—ROIs were placed (Fig 1) in the fetal cerebrum, cerebellum, heart, lungs, liver, and complete cotyledon to enable measurement of signal intensity (U.W.). The human placenta is discoidal and composed of closely aggregated cotyledons. In sheep, the cotyledons are not in one place; instead, they are scattered over the uterine wall. The total of all cotyledons is the equivalent of the human placenta. ROI placement is possible in only one cotyledon. In each organ, a reference section was selected to allow at least one adjacent section above and below the reference section and to attain a reasonable ROI size of at least 100 pixels, if possible. Average ROI size was 267 pixels (range, 187–346 pixels) for the cerebrum, 94 pixels (range, 35–154 pixels) for the cerebellum, 399 pixels (range, 242–556 pixels) for the lungs, 314 pixels (range, 54–574 pixels) for the liver, 210 pixels (range, 136–284 pixels) for the heart, and 126 pixels (range, 45–207 pixels) for the cotyledon.

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: Transverse T2*-weighted single-shot gradient-echo echo-planar MR images (echo time, 30 msec; field of view, 180 mm; acquired spatial resolution, 2.25 x 2.25 mm; reconstructed resolution, 1.4 x 1.4 mm; acquired matrix, 80 x 80; reconstructed matrix, 128 x 128; section thickness, 5 mm; intersection gap, 1 mm; flip angle, 90°) of the fetal (a) cerebrum, (b) heart, (c) lungs, (d) liver, and (e) cotyledon of animal 2. Images were obtained during the control period with 99% maternal oxyhemoglobin saturation and 68% fetal oxyhemoglobin saturation. (a, b, d) Note the ROIs (white dotted line). (c) ROI placement in the lung with and without large vessels (white dotted line). (e) ROI placement in the cotyledon, including the complete (black dotted line), central (white dotted line), and peripheral (white solid line) parts.

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: Transverse T2*-weighted single-shot gradient-echo echo-planar MR images (echo time, 30 msec; field of view, 180 mm; acquired spatial resolution, 2.25 x 2.25 mm; reconstructed resolution, 1.4 x 1.4 mm; acquired matrix, 80 x 80; reconstructed matrix, 128 x 128; section thickness, 5 mm; intersection gap, 1 mm; flip angle, 90°) of the fetal (a) cerebrum, (b) heart, (c) lungs, (d) liver, and (e) cotyledon of animal 2. Images were obtained during the control period with 99% maternal oxyhemoglobin saturation and 68% fetal oxyhemoglobin saturation. (a, b, d) Note the ROIs (white dotted line). (c) ROI placement in the lung with and without large vessels (white dotted line). (e) ROI placement in the cotyledon, including the complete (black dotted line), central (white dotted line), and peripheral (white solid line) parts.

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 1c: Transverse T2*-weighted single-shot gradient-echo echo-planar MR images (echo time, 30 msec; field of view, 180 mm; acquired spatial resolution, 2.25 x 2.25 mm; reconstructed resolution, 1.4 x 1.4 mm; acquired matrix, 80 x 80; reconstructed matrix, 128 x 128; section thickness, 5 mm; intersection gap, 1 mm; flip angle, 90°) of the fetal (a) cerebrum, (b) heart, (c) lungs, (d) liver, and (e) cotyledon of animal 2. Images were obtained during the control period with 99% maternal oxyhemoglobin saturation and 68% fetal oxyhemoglobin saturation. (a, b, d) Note the ROIs (white dotted line). (c) ROI placement in the lung with and without large vessels (white dotted line). (e) ROI placement in the cotyledon, including the complete (black dotted line), central (white dotted line), and peripheral (white solid line) parts.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 1d: Transverse T2*-weighted single-shot gradient-echo echo-planar MR images (echo time, 30 msec; field of view, 180 mm; acquired spatial resolution, 2.25 x 2.25 mm; reconstructed resolution, 1.4 x 1.4 mm; acquired matrix, 80 x 80; reconstructed matrix, 128 x 128; section thickness, 5 mm; intersection gap, 1 mm; flip angle, 90°) of the fetal (a) cerebrum, (b) heart, (c) lungs, (d) liver, and (e) cotyledon of animal 2. Images were obtained during the control period with 99% maternal oxyhemoglobin saturation and 68% fetal oxyhemoglobin saturation. (a, b, d) Note the ROIs (white dotted line). (c) ROI placement in the lung with and without large vessels (white dotted line). (e) ROI placement in the cotyledon, including the complete (black dotted line), central (white dotted line), and peripheral (white solid line) parts.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 1e: Transverse T2*-weighted single-shot gradient-echo echo-planar MR images (echo time, 30 msec; field of view, 180 mm; acquired spatial resolution, 2.25 x 2.25 mm; reconstructed resolution, 1.4 x 1.4 mm; acquired matrix, 80 x 80; reconstructed matrix, 128 x 128; section thickness, 5 mm; intersection gap, 1 mm; flip angle, 90°) of the fetal (a) cerebrum, (b) heart, (c) lungs, (d) liver, and (e) cotyledon of animal 2. Images were obtained during the control period with 99% maternal oxyhemoglobin saturation and 68% fetal oxyhemoglobin saturation. (a, b, d) Note the ROIs (white dotted line). (c) ROI placement in the lung with and without large vessels (white dotted line). (e) ROI placement in the cotyledon, including the complete (black dotted line), central (white dotted line), and peripheral (white solid line) parts.

Statistical Analysis
Because BOLD images and maternal data were not collected at exactly the same time, maternal data were linearly interpolated from the mean of two values immediately before and after BOLD imaging and were assigned the same time as the BOLD image. There was a short interval between maternal oxyhemoglobin saturation measurements (sample rate, 0.39 per second), and the maternal oxyhemoglobin saturation level was constant within the plateau. The merged and adjusted data sets were saved as text files for statistical analysis (Statistica; Statsoft, Tulsa, Okla).

Mean values with 95% confidence intervals of the BOLD signal intensity percentage and maternal oxyhemoglobin saturation of the control and hypoxic phases were calculated. Linear regression analysis and correlation of the BOLD signal intensity percentage with maternal and fetal oxyhemoglobin saturation were performed. For variation of ROI placement, differences in BOLD signal intensity between the ROI settings were calculated with analysis of variance and expressed as percentage differences. A paired t test was used to evaluate differences. Differences were considered statistically significant if the P value was less than .05. The theoretical assumption of the t test and analysis of variance is that paired differences should be distributed normally. Hypoxic BOLD signal intensity percentages were normally distributed.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Fetal blood samples and heart rates were obtained in all animals, with the exception of animal 1 (Table 1); in this animal, the catheter was not viable.

View larger version (47K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Scatterplots constructed with data from animal 4 show findings of a hypoxic phase with an initial control period, hypoxia after reduction of the maternal oxyhemoglobin saturation (MatSO2), and recovery. Time course of (a) absolute and (b) normalized BOLD signal intensities (BOLD SI and BOLD SI%, respectively) of the cerebrum, cerebellum, lungs, cotyledon, liver, heart, and maternal oxyhemoglobin saturation. Fetal blood samples were obtained during the control and hypoxic phases (arrows in a). FetSO2 = fetal oxyhemoglobin saturation.

View larger version (39K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Scatterplots constructed with data from animal 4 show findings of a hypoxic phase with an initial control period, hypoxia after reduction of the maternal oxyhemoglobin saturation (MatSO2), and recovery. Time course of (a) absolute and (b) normalized BOLD signal intensities (BOLD SI and BOLD SI%, respectively) of the cerebrum, cerebellum, lungs, cotyledon, liver, heart, and maternal oxyhemoglobin saturation. Fetal blood samples were obtained during the control and hypoxic phases (arrows in a). FetSO2 = fetal oxyhemoglobin saturation.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 3a: Linear regression of BOLD signal intensity for (a, b) cerebrum, (c, d) heart, and (e, f) cotyledon with maternal (MatSO2) and fetal (FetSO2) oxyhemoglobin saturation. Mean values of the hypoxic plateaus are marked for each animal (animal 2, ; animal 3, ; animal 4, ; animal 5, ; animal 6, ). Dashed lines indicate the 95% confidence interval of the regression line.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 3b: Linear regression of BOLD signal intensity for (a, b) cerebrum, (c, d) heart, and (e, f) cotyledon with maternal (MatSO2) and fetal (FetSO2) oxyhemoglobin saturation. Mean values of the hypoxic plateaus are marked for each animal (animal 2, ; animal 3, ; animal 4, ; animal 5, ; animal 6, ). Dashed lines indicate the 95% confidence interval of the regression line.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 3c: Linear regression of BOLD signal intensity for (a, b) cerebrum, (c, d) heart, and (e, f) cotyledon with maternal (MatSO2) and fetal (FetSO2) oxyhemoglobin saturation. Mean values of the hypoxic plateaus are marked for each animal (animal 2, ; animal 3, ; animal 4, ; animal 5, ; animal 6, ). Dashed lines indicate the 95% confidence interval of the regression line.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 3d: Linear regression of BOLD signal intensity for (a, b) cerebrum, (c, d) heart, and (e, f) cotyledon with maternal (MatSO2) and fetal (FetSO2) oxyhemoglobin saturation. Mean values of the hypoxic plateaus are marked for each animal (animal 2, ; animal 3, ; animal 4, ; animal 5, ; animal 6, ). Dashed lines indicate the 95% confidence interval of the regression line.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 3e: Linear regression of BOLD signal intensity for (a, b) cerebrum, (c, d) heart, and (e, f) cotyledon with maternal (MatSO2) and fetal (FetSO2) oxyhemoglobin saturation. Mean values of the hypoxic plateaus are marked for each animal (animal 2, ; animal 3, ; animal 4, ; animal 5, ; animal 6, ). Dashed lines indicate the 95% confidence interval of the regression line.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 3f: Linear regression of BOLD signal intensity for (a, b) cerebrum, (c, d) heart, and (e, f) cotyledon with maternal (MatSO2) and fetal (FetSO2) oxyhemoglobin saturation. Mean values of the hypoxic plateaus are marked for each animal (animal 2, ; animal 3, ; animal 4, ; animal 5, ; animal 6, ). Dashed lines indicate the 95% confidence interval of the regression line.

Comparing ROI measurements in different section levels, BOLD signal intensity changed 1%–2% for the heart and lungs and 5% for the liver in the adjacent sections. These differences were not significant.

At comparison of ROI measurements in the lungs with and without large pulmonary vessels, differences in BOLD signal intensity were 2% for both lungs and 3% and 4% for the left and right lungs, respectively. Differences were significant for the right lung (P < .001).

The mean difference in BOLD signal intensity varied by as much as 2% between measurements in the central, peripheral, and complete cotyledon. BOLD signal intensities were as follows: complete cotyledon, 64% (range, 57%–71%); center cotyledon, 63% (range, 48%–79%); and peripheral cotyledon, 65% (range, 56%–75%).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Our results show that fetal BOLD MR imaging reflects changes in the fetal blood induced by alterations in the maternal oxyhemoglobin saturation. There is a relationship between changes in maternal oxyhemoglobin saturation and fetal BOLD signal intensity. Despite significant correlations of BOLD signal intensity with maternal oxyhemoglobin saturation (cerebrum, r = 0.68), one must consider that the maternal and fetal circulations are separate entities. Supposing that BOLD signal intensity depends on fetal blood oxygenation, one would expect a closer correlation of BOLD signal intensity with fetal oxyhemoglobin saturation than with maternal oxyhemoglobin saturation. This is consistent with the fact that correlations were higher (though not significantly higher) with fetal oxyhemoglobin saturation (cerebrum: r = 0.91) than with maternal oxyhemoglobin saturation in our study. BOLD signal intensities of cotyledons were correlated equally well with maternal (r = 0.79) and fetal (r = 0.77) oxyhemoglobin saturation; this might be because a cotyledon contains both fetal and maternal blood.

Differences in BOLD Signal Intensity between Fetal Organs
Decreases in maternal blood oxyhemoglobin saturation are reflected by decreases in BOLD signal intensity not only in the fetal brain but also in the fetal liver, lungs, heart, and cotyledon. There were considerable differences between two groups of fetal organs, with a greater signal intensity decrease in the liver and heart (ie, 40%) than in the brain and lungs (ie, 19%). Similar results were reported in a previous pilot animal study (10). Additionally, fetal organ BOLD MR imaging was used to demonstrate changes in the cotyledon with an average decrease in BOLD signal intensity of 30%. For the interpretation of different BOLD signal intensity changes in blood oxygenation in fetal organs, it must be considered that BOLD signal intensity changes depend on (a) changes in blood oxygenation, (b) differences in the fractional blood volume between the organs, and (c) changes in fractional blood volume (11,12).

During hypoxia, there is a redistribution of fetal blood flow that is demonstrated both in animals and in humans to increase blood flow selectively to organs that are essential for survival (eg, brain, myocardium, adrenal glands) at the expense of the lower part of the body (eg, circulatory centralization) (13–15). Blood flow to essential organs increases two- to threefold (16,17). Thus, oxygenation changes should be smaller in the brain than in the liver. Assuming that changes in oxygenation are the dominant effect and that there are only small changes in oxygen consumption and blood volume, we expect BOLD signal intensity changes to be smaller in the fetal brain, myocardium, and adrenal glands than in another fetal organ, such as the liver. In fact, the fetus can reduce its oxygen consumption by about one-third during hypoxia without developing acidosis. In essential organs, oxygen consumption remains constant because blood flow increases. Other organs adapt to the reduced oxygen supply by reducing oxygen consumption (18).

In our study, the signal intensity decrease was greater in the liver (40%) than in the brain (20%). Signal intensity changes in the heart, despite the increased myocardial blood flow, resulted from the fact that we did not measure the effect of blood in the myocardium; however, signal intensity changes occurred predominantly because of the presence of fetal blood in the cardiac chambers. Selective ROI measurements were not possible because of thin myocardium and cardiac motion artifacts. The cause of the less severe signal intensity decrease seen in the fetal lungs remains unclear; however, it might be explained by the fact that signal intensity in the lungs was predominantly a product of fluid in the lungs and was only partially influenced by the blood in nearby vessels.

The same change in blood oxygenation in a tissue with a large blood fraction causes a larger change in BOLD signal intensity than in a tissue with a small blood fraction. The amount of fractional blood volumes in the fetal organs is mainly unknown, but circulating blood volume decreases by up to 14% during acute hypoxia in fetal sheep (19). The fetal sheep liver contains about 10%–15% of the fetal blood volume and serves as a major blood reservoir for the fetus (20). In adult sheep, the liver receives about one-third of the cardiac output, and blood occupies 25%–30% of the liver volume (21); this volume might be higher than that in the brain. In the fetus, there is probably a larger fractional blood volume in the liver than in the brain. Assuming that differences in the total amount of blood volume in the organs is the dominant effect, we would expect greater signal intensity changes in organs with a larger proportion of blood volume. Our results show greater signal intensity changes in the liver and heart than in the brain and lungs. On the basis of this assumption, we speculate that there are smaller signal intensity changes in the lungs because the blood volume fraction of the lungs is presumably small before birth.

It has been proved that changes in tissue fractional blood volume alone can result in substantial changes in BOLD signal intensity, independent of changes in oxyhemoglobin saturation (22,23). This phenomenon was observed in hypercapnia (22,23), whereas the influence of blood volume alterations on BOLD signal intensity during hypoxia seems to be of minor concern (11). It is known that accelerated blood flow to the brain with dilatation of the cerebral arterioles during hypoxia leads to increased cerebral blood volume (24,25). Because of the increased blood flow to the essential organs and decreased blood flow to the other organs, we would expect to see an increased blood volume in the brain and a decreased blood volume in the liver and lungs. In theory, an increase in blood volume and, concomitantly, an increase in deoxyhemoglobin during hypoxia would induce a stronger decrease in BOLD signal intensity. Thus, assuming that blood volume changes during hypoxia are the dominant effect, there should be stronger signal intensity decreases in the brain than in the liver and lungs. However, our results show that the largest signal intensity decreases occur in the liver and the smallest signal intensity decreases occur in the brain; this finding is in concordance with the physiologic reaction during hypoxia. Thus, we do not think that BOLD signal intensity changes are mainly induced by changes in the blood volume.

In summary, we assume that decreases in BOLD signal intensity in the fetal organs, which have been demonstrated in all experiments, mainly rely on alterations of the deoxyhemoglobin concentration during hypoxia. Different signal intensity changes in different fetal organs may indicate that different organs receive different oxygen supplies during hypoxia. The oxygen supply seems to be consistent for the brain and liver. However, signal intensity changes may also be influenced by differences in the fractional blood volumes. Proportions of changes in blood volume are unknown. To investigate this in further detail, experiments are needed in which blood volume changes in different organs during hypoxia are measured; experiments are also needed to assess the proportion of total blood in different organs in the fetus.

Limitations
One limitation of this study was the small number of animals and experiments. Furthermore, the experimental setting with surgery and anesthesia might have affected our results. Responses to hypoxemia could have been modified by the effects of the anesthetic agents used. Since adjustments induced by the sympathetic nervous system and adrenal gland are important in the response to hypoxia, a fetus that is already acutely stressed by the experimental procedure could have a different level of sympathetic nervous system and adrenal gland activity, which may influence the response to superimposed hypoxemia (16). It is also known that surgical intervention in the fetal lamb in utero may influence certain physiologic functions (26). To reduce these difficulties, we performed the experiments 4–7 days after surgery to allow for recovery from the manipulations. Finally, the long-lasting nonphysiologic experimental situation during BOLD measurement (eg, general anesthesia with artificial ventilation, lateral position of the ewe) may affect maternal and fetal oxygen exchange in the placenta and oxygen distribution in the fetus to various degrees.

In general, we must mention that our results are based on findings in fetal sheep and might not be easily transferable to humans. This is especially true for the comparison of the sheep cotyledon with the human placenta.

Practical Applications: BOLD MR imaging shows potential in the noninvasive demonstration of blood oxygenation changes in fetal sheep organs—such as the brain, lungs, liver, and heart—during hypoxia. We assume that the BOLD signal intensity decreases that occurred during hypoxia (eg, 40% in the fetal liver and heart; 20% in the fetal brain and lungs) reflected predominant changes in blood oxygenation and differences in the fractional blood volume of these organs. For practical applications in fetal surveillance, the liver and heart seem to be most sensitive to changes in fetal tissue oxygenation because of strong decreases in signal intensity.

	ACKNOWLEDGMENTS

 
The authors thank the Deutsche Forschungsgemeinschaft for financial support of this study.

	FOOTNOTES

 

Abbreviations: BOLD = blood oxygen level dependent • ROI = region of interest

See also Science to Practice in this issue.

Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, H.K., G.A., H.J.S.; experimental studies, U.W., M.T., S.S., A.N.P., H.K., H.J.S.; statistical analysis, U.W., H.J.S.; and manuscript editing, U.W., M.T., A.N.P., H.K., G.A., H.J.S.

	References

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 

1. Shinmoto H, Kuribayashi S. MRI of fetal abdominal abnormalities. Abdom Imaging 2003;28:877–886.[Medline]
2. Matsuoka S, Takeuchi K, Yamanaka Y, Kaji Y, Sugimura K, Maruo T. Comparison of magnetic resonance imaging and ultrasonography in the prenatal diagnosis of congenital thoracic abnormalities. Fetal Diagn Ther 2003;18:447–453.[CrossRef][Medline]
3. Caire JT, Ramus RM, Magee KP, Fullington BK, Ewalt DH, Twickler DM. MRI of fetal genitourinary anomalies. AJR Am J Roentgenol 2003;181:1381–1385.[Abstract/Free Full Text]
4. Ghi T, Tani G, Savelli L, Colleoni GG, Pilu G, Bovicelli L. Prenatal imaging of facial clefts by magnetic resonance imaging with emphasis on the posterior palate. Prenat Diagn 2003;23:970–975.[CrossRef][Medline]
5. Malinger G, Ben-Sira L, Lev D, Ben-Aroya Z, Kidron D, Lerman-Sagie T. Fetal brain imaging: a comparison between magnetic resonance imaging and dedicated neurosonography. Ultrasound Obstet Gynecol 2004;23:333–340.[CrossRef][Medline]
6. Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 1990;87:9868–9872.[Abstract/Free Full Text]
7. Ogawa S, Menon RS, Tank DW, et al. Functional brain mapping by blood oxygenation level dependent contrast magnetic resonance imaging. Biophys J 1993;64:803–812.[Abstract/Free Full Text]
8. Ogawa S, Tank D, Menon RS. Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc Natl Acad Sci U S A 1992;89:5951–5955.[Abstract/Free Full Text]
9. Belliveau JW, Kennedy DN Jr, McKinstry RC, et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 1991;254:716–719.[Abstract/Free Full Text]
10. Wedegärtner U, Tchirikov M, Koch M, Adam G, Schröder H. Functional magnetic resonance imaging (fMRI) for fetal oxygenation during maternal hypoxia: initial results. Rofo 2002;174:700–703.[Medline]
11. Lin W, Celik A, Paczynski RP, Hsu C, Powers W. Quantitative magnetic resonance imaging in experimental hypercapnia: improvement in the relation between changes in brain R2* and the oxygen saturation of venous blood after correction of changes in cerebral blood volume. J Cereb Blood Flow Metab 1999;19:853–862.[CrossRef][Medline]
12. Foley LM, Picot P, Thompson RT, Yau MJ, Brauer M. In vivo monitoring of hepatic oxygenation changes in chronically ethanol-treated rats by functional magnetic resonance imaging. Magn Reson Med 2003;50:976–983.[CrossRef][Medline]
13. Rizzo G, Arduini D. Fetal cardiac function in intrauterine growth retardation. Am J Obstet Gynecol 1991;165:876–882.[Medline]
14. Hecher K, Campbell S, Doyle P, Harrington K, Nicolaides K. Assessment of fetal compromise by Doppler ultrasound investigation of the fetal circulation. Circulation 1995;91:129–138.[Abstract/Free Full Text]
15. Al-Ghazali W, Chita SK, Chapman MG, Allan LD. Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obstet Gynaecol 1989;96:697–704.[Medline]
16. Cohn HE, Sacks EJ, Heymann MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol 1974;120:817–824.[Medline]
17. Jensen A, Berger R. Fetal circulatory responses to oxygen lack. J Dev Physiol 1991;16:181–207.[Medline]
18. Polin RA, Fox WW. Fetal and neonatal physiology. Philadelphia, Pa: Saunders, 1998; 1014–1021.
19. Brace RA. Fetal blood volume responses to acute fetal hypoxia. Am J Obstet Gynecol 1986;155:889–893.[Medline]
20. Gilbert RD, Genstler CC, Dale PS, Power GG. Compliance of the fetal sheep liver. J Dev Physiol 1981;3:283–295.[Medline]
21. Macdonald JM, Schmidlin O, James TL. In vivo monitoring of hepatic glutathione in the anesthetized rats by 13C NMR. Magn Reson Med 2002;48:430–439.[CrossRef][Medline]
22. Jezzard P, Heineman F, Taylor J, et al. Comparison of EPI gradient-echo contrast changes in cat brain caused by respiratory challenges with direct simultaneous evaluation of cerebral oxygenation via a cranial window. NMR Biomed 1994;7:35–44.[Medline]
23. Kennan RP, Scanley BE, Gore JC. Physiological basis of BOLD MR signal changes due to hypoxia/hyperoxia: separation of blood volume and magnetic susceptibility effects. Magn Reson Med 1997;37:953–956.[Medline]
24. Julien-Dolbec C, Tropres I, Montigon O, et al. Regional response of cerebral blood volume to graded hypoxic hypoxia in rat brain. Br J Anaesth 2002;89:287–293.[Abstract/Free Full Text]
25. Kontos HA, Wei EP, Raper AJ, Rosenblum WI, Navari RM, Patterson JL. Role of tissue hypoxia in local regulation of cerebral microcirculation. Am J Physiol 1978;234:H582–H591.[Medline]
26. Dawes GS, Fox HE, Leduc BM, Liggins GC, Richards RT. Respiratory movements and rapid eye movement sleep in the foetal lamb. J Physiol 1972;220:119–143.[Abstract/Free Full Text]

This article has been cited by other articles:

				J. V. Ilekis, U. M. Reddy, and J. M. Roberts Review Article: Preeclampsia A Pressing Problem: An Executive Summary of a National Institute of Child Health and Human Development Workshop Reproductive Sciences, September 1, 2007; 14(6): 508 - 523. [Abstract] [PDF]

This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2383042213v1 238/3/872    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wedegärtner, U. Articles by Schröder, H. J. Search for Related Content PubMed PubMed Citation Articles by Wedegärtner, U. Articles by Schröder, H. J.