Magnesium sulfate has become one of the most commonly used drugs in American obstetrics. Indications for use have included management of eclampsia, tocolytic treatment of preterm labor, and, most recently, prevention of brain damage in very low birth weight (less than 1,500 g) neonates.1–4 The reported cerebral protective effects include prevention of cerebral hemorrhage in the neonatal period as well as cerebral palsy during infancy.1–4 Hypothesized pathways of brain injury in very low birth weight neonates include precluding hypoxic–ischemic injury with reperfusion intracerebral bleeding in the first 2–3 days of life and fluctuations in cerebral blood flow associated with neonatal interventions such as mechanical ventilation.5–7 The protection against brain injury has been hypothesized to be due to blockade of N-methyl-d-aspartate receptors, by the attenuation of vasoactivity by blockade of calcium channels, and, lastly, by direct arterial dilation by the magnesium ion.8–13
Our purpose was to measure Doppler flow indices in the fetal cerebral circulation to determine whether this methodology could estimate magnesium-sulfate induced changes in the cerebral blood flow.
MATERIALS AND METHODS
This is a single-center ancillary of a multicenter, placebo-controlled, double-blind trial from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.1 A total of 2,241 women at imminent risk of preterm delivery were allocated randomly to receive magnesium sulfate or placebo. Details about the inclusion/exclusion criteria, the allocation, and masking are described by Rouse et al.1 Group assignment was accomplished using a computer-generated urn method to maintain balance over time. Patients qualified for inclusion if they were carrying singletons or twins at 24 to 31 weeks and were at high risk for spontaneous delivery. In keeping with the protocol, the study was approved by our institutional review board and informed patient consent was obtained. Blinded randomization to intravenous placebo or magnesium sulfate was assigned to 38 women in preterm labor between 24 and 31 weeks of gestation. For this ancillary study, patients were enrolled consecutively from May 31, 1998, through April 11, 1999. For those in the magnesium-sulfate group, 6 g dilute magnesium sulfate was given intravenously over 20 minutes, followed by a continuous infusion of 2 g/h.
The middle cerebral artery Doppler technique was similar to that employed to evaluate fetal anemia.14,15 Fetal cerebral circulation was measured at the level of the Circle of Willis using a 3-Mhz curved linear transducer with color Doppler energy rainbow images (settings 35 dB, EI+4; Acuson 128XP, Mountain View, CA).
Three measurements of proximal middle cerebral artery width were obtained and averaged. Next, the spectral Doppler cursor was placed on the middle cerebral artery within 1 mm of the proximal vessel branch and three acquisitions were obtained for measurements of maximum systole, end diastole, and time-average maximum velocity from spectral waveforms obtained by transducers that were positioned so as to minimize the angle of insonation and need for correction. Fetal heart rate during each acquisition also was calculated. Blood volume flow was calculated using the equation pi r2 (cm2)×60 s/min×mean velocity (cm/s). Doppler evaluation was performed before administration of magnesium sulfate to the mother and repeated at 1-, 2-, 3-, and 4-hour intervals (Fig. 1).
The sample size selected was based on unpublished pilot data concerning 19 pregnancies at our institution. All 19 patients were given magnesium sulfate. There was no control arm for these observations. We observed a mean decrease in middle cerebral artery flow from 53 cc/min (standard deviation [SD] 21) to 40 cc/min (SD 16) P<.001 and a decrease in peak systolic velocity from 46 cm/s (SD 11) to 38 cm/s (SD 14) P=.03. The SD of the middle cerebral artery flow difference was 12 cm/s. We then chose a sample size of 19 patients per arm (38 total) to compare patients receiving magnesium sulfate with a similar change in flow with a placebo arm assumed to have no change in flow over the time course (80% power, two-sided test of significance level 0.05 under a Student t test).
Repeated-measures random-effects modeling was performed using PROC MIXED in SAS 9 (SAS Institute, Cary, NC). Specifically, values represent the least squares mean estimated from a random-effects model with a repeated-measures design. Time is the repeated measure and is a random effect using a Toeplitz structure for the covariance estimates. Specifically, values represent the least squares mean estimated from a random-effects model with a repeated-measures design using a Toeplitz structure for the covariance estimates. The Toeplitz structure assumes, for estimation purposes, that the covariance is the same for each lag of the time difference.
Treatment assignment (magnesium sulfate or placebo) is a fixed effect. The estimates are adjusted for the continuous fixed effect of gestational age at Doppler and the time-varying effect of vessel width. P values are from the cross-sectional contrasts examining the hypothesis of no difference between magnesium sulfate and placebo means at the epochs. In addition, χ2 and Student t test were used.
A total of 38 fetuses were studied: 18 received magnesium sulfate and 20 received placebo. Demographics are presented in Table 1. Peak systolic velocity was significantly associated with gestational age (P<.001) (Fig. 2), as were time-average velocity and calculated volume flow (P<.001). However, there was no difference in the peak systolic velocity measurements (P=.19), calculated volume flow (P=.39), mean time-average maximum velocity (P=.68), or vessel diameter (P=.89) at hourly intervals between the magnesium-sulfate and placebo groups. The interaction between time and treatment assignments was also not significant for the peak systolic velocity (P=.52). The mean fetal heart rate was significantly decreased after the administration of magnesium sulfate compared with the placebo group (P=.005) (Fig. 3).
We found no changes in the middle cerebral artery Doppler parameters measured when comparing those who received magnesium sulfate with those in the placebo control group. Parameters included peak systolic velocity, time-average maximum velocity, vessel diameter, and calculated volume flow. There was, however, a significant decrease of between 8 and 10 beats per minute (bpm) in the fetal heart rate measured from the Doppler waveforms. This finding of decreased fetal heart rate after the administration of magnesium sulfate compared with placebo is not a new finding; it had been seen in a previous randomized, placebo-controlled trail in which the purpose was to study the effects of magnesium sulfate in fetal heart rate monitoring.16 That study also found a decrease in beat-to-beat variability of heart rate in nonlaboring pregnant women at more than 30 weeks of gestation after the intravenous administration of magnesium sulfate.
The decreased fetal heart rate we observed after administration of magnesium sulfate is an intriguing finding given that intraventricular hemorrhage has been associated with cerebral hyperperfusion from neonatal interventions such as mechanical ventilation.5–7 A recent study found that acceleration of the fetal heart rate is associated with a decrease in the middle cerebral artery peak systolic velocity.17 The decrease of the peak systolic velocity was manifest in that study beyond 27 weeks and when the heart rate exceeded 150 bpm. In our study, the heart rate decreased with magnesium sulfate compared with placebo by between 8 and 10 bpm to a range of 132 to 135 bpm in fetuses with a mean age of approximately 28 weeks after administration of magnesium sulfate, without a change in the peak systolic velocity or calculated volume flow. The difference that we found in our pilot data in the Doppler parameters may be secondary to the average gestational age in that population, which was 30.0 weeks (±2.6), 2 weeks more than our present study group.
The issue of why there was no change in the calculated cerebral blood flow based on Doppler parameters with the significant decrease in fetal heart rate should be addressed. As noted above, it may be that, in our groups, in which mean gestational ages are lower than in our pilot study and other studies, the changes may be too subtle or that the fetus does not respond to heart-rate–related changes earlier in gestation. Indeed, it may have to do with the imprecision of our instrumentation and the complex physiologic factors affecting cerebral blood flow that are not taken into account by this method. Although the equation flow=velocity×area is a reasonable mechanical principle, the physiology of the cerebral-vascular bed is much more complex. This includes the dynamic pressure-flow relationship between arterial blood pressure and intracranial pressure. There are the added effects of the vascular smooth muscle and endothelial cells—complex feedback systems in the cerebral tissue involving metabolic, neurogenic, and myogenic components as well as oxygen extraction capabilities at the cellular level.18 More dramatic cerebral blood flow changes from normal may therefore be required to result in the changes detected by Doppler analysis.
What is significant is the finding of decreased fetal heart rate in preterm fetuses whose mothers receive magnesium sulfate—the opposite of its maternal effect, where magnesium sulfate increases the heart rate. Perhaps it is the sustaining of fetal heart rate in the low-normal range without significant peak systolic velocity changes that protects the very premature neonate from cerebral hyperperfusion. Whatever the mechanism, we are convinced that magnesium sulfate exerts a unique effect on fetal cerebral circulation that may have a role in the neuroprotection now attributed to it.
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