全文

Abstract
Objective
The brain sparing phenomenon in the fetus is a protective mechanism aimed at maintaining sufficient blood flow towards the brain during chronic or acute fetal stress, such as that caused by hypoxemia or utero-placental insufficiency. In this study we investigated whether the brain sparing effect can also be elicited by a physiological stress associated with maternal posture.

Study design Twenty-three low-risk pregnant women participated in the study. Between 36 and 40 weeks’ gestation, Doppler flow velocity waveforms were obtained from the fetal middle cerebral and the umbilical artery in the supine and the left lateral decubitus positions. Pulsatility index, systolic/diastolic index, and peak systolic velocities were measured and comparison was made between the left lateral and supine positions.

Results
The pulsatility index in the middle cerebral artery decreased from 1.78 ± 0.27 in the left lateral decubitus position to 1.29 ± 0.16 in supine position (p < 0.0001). Peak systolic velocity decreased from 46.05 ± 7.85 cm/s to 39.43 ± 7.95 cm/s, respectively (p = 0.001). The pulsatility index in the umbilical artery decreased from 0.89 ± 0.13 in the left lateral position to 0.74 ± 0.11 in the supine position (p < 0.0001).

Conclusions
This study demonstrates that the supine position in late pregnancy, causing aortic and venacaval compression, leads to brain auto-regulation that activates the brain sparing effect in the fetus. This protective mechanism, shown here for the first time to be linked to a physiological stress, may provide the basis for a novel approach in the assessment of fetal wellbeing.

Keywords: Fetal brain sparing, Supine position, Doppler flow velocity wave forms.

Introduction
Fetal brain sparing is a well known phenomenon in obstetrics. It aims to maintain sufficient blood flow towards vital organ such as the brain, myocardium, and adrenals. This vascular adaptation takes place as a result of placental insufficiency that may occur in intrauterine growth restriction (IUGR) and preeclampsia. Animal studies have shown that in cases of IUGR attributable to placental insufficiency, the central nervous system is preferentially perfused, which is intended to maintain the highest degree of oxygen supply to the brain [1] and [2]. Human studies have demonstrated that fetal blood flow redistribution is not limited to pathological conditions. It may occur in association with acute or chronic stress such as hypoxemia or uteroplacental insufficiency and in relation to various maternal positions [3] and [4]. Impaired venous return due to compression of the inferior vena cava by the gravid uterus can also elicit supine hypotensive syndrome, occurring in 10–15% of women [5] and [6]. Maternal supine position in late gestation partially obstructs the aorta, due to the enlarged uterus, and leads to redistribution of blood flow [4] and more nonreactive fetal heart rate traces [8]. Furthermore, supine position was also shown to cause circulatory changes in the fetus. The umbilical artery S/D ratios were significantly higher in the supine than in other lateral positions, indicating that the umbilical artery vascular resistance is increased when the mother changes position [4].

In this study we sought to investigate whether fetal blood redistribution, known as the brain sparing effect, can also be elicited by a physiological stress associated with maternal posture.

Materials and methods
Twenty-three women with low-risk pregnancy, five of them primigravid, participated in the study between 36 and 40 weeks’ gestation. All women had an uneventful current pregnancy, had no history of past medical conditions, were nonsmokers and did not use any drugs or medication apart from iron supplementation.

The study was approved by the local ethics committee and informed consent was obtained from each woman. Gestational age was calculated from the last menstrual period and confirmed by first trimester crown-rump length measurement. When the ultrasonographically determined gestational age differed from the gestational age according to last menstrual period by more than seven days, the pregnancy was dated according to the ultrasonographic scan. The estimated fetal weight was derived from measurements of the head and abdominal circumferences, and from the femur length [8].

For each woman, Doppler flow measurements were obtained from the MCA (pulsatility index and peak systolic velocity) and UA (pulsatility index and systolic/diastolic ratio) following 15 min rest in the left lateral decubitus position. Subsequently, the women were asked to change into the supine position for an additional 15 min, to allow feto-maternal adaptation to the new position, and Doppler measurements were then repeated. The equipment used was a Voluson 730 Pro (GE Healthcare, Solingen, Germany) with a 2–7 MHz curved-array probe. To minimize interobserver error, only one operator (N.K.) performed the Doppler measurements. Doppler flow velocity waveforms were obtained from the fetal middle cerebral and the umbilical artery, during fetal apnea, in the supine and left lateral decubitus positions as described above. At least five good quality flow velocity waveforms were obtained from each vessel and the measurement was repeated twice. Three different measurements were obtained and averaged to derive the final value. Statistical analyses were performed using the SAS statistical package (SAS Institute, Cary NC, USA). The paired t-test was used, with a p value less than 0.05 considered as statistically significant. Results are expressed as the mean ± one standard error of the mean.

 Results
The mean maternal age was 30.82 ± 4.7 years, the mean fetal weight was 3278.1 ± 378.1 g, and the mean gestational age was 38.2 ± 2 weeks. Comparison between the Doppler studies measured in two positions is presented in Table 1. As shown in this table, the pulsatility index in the middle cerebral and the umbilical artery decreased after changing the position from left lateral to supine. Similar changes were obtained measuring the middle cerebral artery peak systolic velocity and the umbilical artery S/D ratio.

Comments
Our study demonstrated that the fetal brain sparing phenomenon is a sensitive mechanism that is not limited to a pathological condition and can be elicited by a physiological stress associated with maternal posture. Fetal brain sparing is a well known mechanism in fetuses with placental insufficiency associated with IUGR. This phenomenon aims to protect the fetus by maintaining sufficient blood flow to the brain when fetal hypoxemia occurs. Vascular resistance of the fetal cerebral circulation decreases, suggesting a circulatory redistribution favouring cerebral blood flow [9] and [10]. Different maternal positions can affect the uterine placental flow, for instance uterine blood flow in the ascending branch of the uterine artery decreases by 34% at supine rest compared to the left lateral position [11]. These changes could compromise fetal oxygenation and elicit the fetal brain sparing effect. Supine position in late pregnancy also interferes with normal lung functions causing lower oxygen tension in maternal blood, while fetal oxygenation decreases [12] and [13].

There have been a number of studies on the association between blood flow velocimetry of the umbilical artery and supine maternal position. Katwijk and Wladimiroff [3] reported that a change in maternal posture from standing to supine position resulted in an increase of the umbilical artery pulsatility index. Marx et al. [14] demonstrated that the umbilical artery systolic/diastolic ratios were significantly higher in women lying in the supine than in the semi-lateral position.

In this study we sought to investigate whether maternal supine position can elicit a brain sparing effect in low risk pregnant women. Our data demonstrate that the pulsatilty index in the middle cerebral artery decreased by changing from left lateral decubitus to supine position. This observation may be explained by aortocaval compression by the gravid uterus which causes the activation of the fetal brain sparing mechanism. Animal studies have shown that compression of the maternal aorta is associated with fetal brain sparing [15] and [16], even during transient acute hypoxia without acidemia over a short time of period [16]. In contrast, the Doppler resistance indices of the umbilical artery declined by changing from left lateral to supine position (Table 1). The latter results contradict other studies [3] which reported an increase in the umbilical artery pulsatility indices consequent to the change of maternal posture from standing to supine position. This elevation in indices may be due to compression effect on the inferior vena cava or the abdominal aorta. Compression on the inferior vena cava or the abdominal aorta may reduce the uterine and placental blood flow which may have similar complications as placental insufficiency. This mechanism may have the same effect on the fetal circulation as IUGR or uterine contractions in active labor. However, Kinsella et al. [17] found no significant difference in the pulsatility index for the umbilical artery between the supine and the left lateral position. Elington et al. [6] also reported no remarkable change of the systolic/diastolic ratio of the umbilical artery between left and right tilted position of less than 10 degrees. Moreover, a remarkable increase of the systolic/diastolic ratio was observed in the left lateral position in some cases [14]. No improvement in the uterine arterial flow has been reported for the left lateral position [17] and [18]. In the pregnant ewe, occlusion of uterine venous flow, with resultant venous congestion in the placental bed, did not affect umbilical artery blood flow [19]. These findings indicate that the compression of the large vessels by the pregnant uterus cannot be suspected to be completely eliminated nor the umbilical arterial flow. These results raise the question whether the occlusion of umbilical artery is affected solely by maternal position or there are other factors, like maternal weight or neural factors, which affect the umbilical artery.

The changes in the Doppler indices were observed in our study 15 min after the change in maternal position, while in previous studies these changes were observed earlier. The relatively late changes observed in our study may be due the time interval required for the fetal circulatory adaptation. The fetal circulatory changes ensure sufficient blood flow to the brain. They probably occur also in women who sleep in supine position and have an uneventful pregnancy outcome. The initial decubitus maternal position in our study as opposed to the initial standing position in previous study may also explain the different results obtained in our study.

To the best of our knowledge this study is the first to demonstrate that fetal brain sparing is linked to physiological stress. Several conclusions can be drawn from our study. It shows that the supine position in late pregnancy is associated with significant reduction in the resistance to flow in the middle cerebral artery. This brain auto-regulation that activates fetal brain sparing is elicited here in response to a physiologic “stress”. The stress involved, acutely decreased uteroplacental perfusion associated with supine posture, is caused by aortocaval compression and a decrease in maternal cardiac output and stroke volume. The pulsatility index in the umbilical artery significantly fell in the supine position due to a compensatory mechanism aimed at improving feto-placental perfusion during a sudden drop in utero-placental blood flow.

Our study demonstrates that the brain sparing phenomenon can be activated by a physiological “stress”. It emphasizes the high sensitivity of this protective mechanism that is aimed at maintaining sufficient blood flow to the brain even during modest decreases in utero-placental perfusion. Our findings provide novel insights into the provocation of fetal brain sparing linked to a physiological stress, which may provide the basis for a novel approach in the assessment of fetal wellbeing.

Condensation
Maternal supine position in late pregnancy induces a brain sparing effect in the fetus.

References
[1] A.A. Baschat. Fetal responses to placental insufficiency: an update. BJOG. 2004;111:1031-1041
[2] H.E. Cohn, E.J. Sacks, M.A. Heymann, et al. Cardiovascular response to hypoxemia and academia in fetal lambs. Am J Obstet Gynecol. 1974;120:817-824
[3] C. Katwijk, J.W. Wladimiroff. Effect of maternal posture on the umbilical flow velocity waveform. Ultrasound Med Biol. 1991;17:683-685
[4] E. Ryo, T. Okai, K. Takagi, et al. Comparison of umbilical artery Doppler velocimetry between maternal supine position and complete left lateral position in predicting obstetric complications. Ultrasound Obstet Gynecol. 1998;11:415-418
[5] B.K. Howard, J.H. Goodson, W. Mengert. Supine hypotensive syndrome in late pregnancy. Obstet Gynecol. 1953;1:371-377
[6] C. Elington, V.L. Katz, W.J. Watson, F.J. Spielman. The effect of lateral tilt on maternal and fetal hemodynamic variables. Obstet Gynecol. 1991;77:201-203
[8] F.P. Hadlock, R.B. Harrist, R.J. Carpenter. Sonographic estimation of fetal weight: the value of femur length in addition to head and abdomen measurements. Radiology. 1984;150:535-540
[9] J.W. Wladimiroff, S. Degani, M.J. Noordam, et al. Cerebral and umbilical aterial blood flow wave forms in normal and growth retarded pregnancies. Obstet Gynecol. 1987;69:705-709
[10] J. Van Eyck, J.W. Wladimiroff, M.J. Noordam, et al. The blood flow waveforms in fetal internal carotid artery and umbilical artery, its relation to fetal behavioral states in growth retarded fetus at 37–38 weeks. Br J Obstet Gynecol. 1988;95:473-477
[11] R.M. Jeffreys, W. Stepanchak, B. Lopez, J. Hardis, J.F. Clapp 3rd. Uterine blood flow during supine rest and exercise after 28 weeks of gestation. BJOG. 2006;113:1239-1247 Crossref.
[12] P. Tamas, A. Szilagyi, S. Jeges, et al. Effects of maternal central hemodynamics on fetal heart rate patterns. Acta Obstet Gynecol Scand. 2007;86:711-714 Crossref.
[13] K. Spiropoulos, E. Prodromaki, V. Tsapanos. Effect of body position on PaO2 and PaCO2 during pregnancy. Gynecol Obstet Invest. 2004;58:22-25 Crossref.
[14] G.F. Marx, S. Patel, J.A. Berman, G. Farmakides, Schulman. Umbilical blood flow velocity waveforms in different maternal position with epidural analgesia. Obstet Gynecol. 1986;68:61-64
[15] P. Malcus, P. Hokegard, I. Kjellmer, G. Lingman, K. Marsal, K. Rosen. The relationship between arterial blood velocity and acid-base status in fetal lamb during experimental asphyxia. J Matern Fetal Invest. 1991;1:29-34
[16] P. Arbeille, D. Maulik, A. Fignon, et al. Assessment of the fetal PO2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol. 1995;21:861-870 Crossref.
[17] S.M. Kinsella, A. Lee, J.A.D. Spencer. Maternal and fetal effects of the supine and pelvic tilt positions in late pregnancy. Eur J Obstet Gynecol Reprod Biol. 1990;36:11-17 Crossref.
[18] F.R. Witter, R.E. Besinger. The effect of maternal position on uterine artery flow during antepartum fetal heart testing. Am J Obstet Gynecol. 1989;160:379-380 Crossref.
[19] W. Berman, R.C. Goodlin, A.M. Heymann, A.M. Rudolph. Relationship between pressure and flow in the umbilical and uterine circulation of the sheep. Circ Res. 1976;38:262-266 Crossref.