Doppler ultrasound assessment of the middle cerebral artery peak systolic velocity (MCA-PSV) has evolved as the standard for the detection of fetal anemia in pregnancies complicated by maternal red cell alloimmunization.1 Estimation of the MCA-PSV allows for a noninvasive method to detect the presence of moderate-to-severe fetal anemia. Normative data from retrospective, cross-sectional studies of the fetal MCA-PSV Doppler have established a threshold value of 1.5 multiples of the median (MoM) for the detection of moderate-to-severe fetal anemia.2,3 Prospective evaluations have demonstrated false-positive rates of 13% and 18%, respectively. Sallout et al4 noted that an active fetal behavioral state was associated with a significant increase in the MCA-PSV as compared with the fetal resting state. The authors advised that the fetal behavioral state be taken into account when undertaking the measurement of the MCA-PSV in an effort to prevent a false-positive result. Based on these data, we hypothesized that an increased fetal heart rate above expected normal ranges for any given gestational age would have an effect on MCA-PSV. We sought to estimate whether an increase of the fetal basal heart rate was associated with an increase in the MCA-PSV.
MATERIALS AND METHODS
A prospective, longitudinal cohort study was conducted to compare Doppler ultrasound measurements of the MCA-PSV obtained at the fetal basal heart rate and during a period of increased fetal heart rate. The institutional review board of the University of North Carolina approved this study. Healthy women without medical comorbidities were recruited from December 2006 to November 2007 at the University of North Carolina Specialty Women’s Center at Rex Hospital, a multidisciplinary women’s referral center located in Raleigh, NC. Women with preexisting conditions, including hypertension, diabetes, and thyroid disease, were excluded from participation. A medication inventory was not conducted on the study participants. It is possible that medications that could affect fetal heart rate may have been taken by patients in the study population. Patients between 14 and 36 weeks of gestation were enrolled. Fetuses with anomalies, known aneuploidy, or intrauterine growth restriction were excluded from the study. Multiple gestations and patients with red cell sensitization were not eligible for participation. Written informed consent was obtained from each study participant before or at the time of the first study visit. Gestational age was confirmed by first-trimester ultrasonography in all subjects. Ultrasonograms were obtained every 4 weeks on each participant, beginning at 16–20 weeks through 34–38 weeks gestational age, totaling five study ultrasonograms. Standard biometric measures were also obtained at each visit. An estimated fetal weight of less than 10% for gestational age using the formula of Hadlock et al5 was used to define intrauterine growth restriction. Ultrasonograms were obtained using a 2.0–7.0 MHz convex transducer on the GE Voluson Expert (GE Medical Systems, Milwaukee, WI) by a single operator (A.E.S.).
Pulsed Doppler ultrasonography was used to obtain a series of two separate MCA waveforms at the proximal segment of the near-field MCA at a 0-degree angle of insonation. Fetal heart rate was measured on the same spectral waveform as the initial MCA-PSV measurement. After initial MCA-PSV, vibroacoustic stimulation was applied to the maternal abdomen in the region of the fetal head for a period of 3 seconds. A second series of MCA waveforms was then obtained, and MCA-PSV and fetal heart rate were again measured. All MCA-PSV and fetal heart rate measurements were acquired manually for each of the waveforms in the series. The mean of the two MCA-PSV and fetal heart rates obtained before vibroacoustic stimulation was used as the initial MCA-PSV and basal fetal heart rate. The mean of the two MCA-PSV measurements and fetal heart rates acquired after vibroacoustic stimulation was then obtained in a similar fashion.
Images of all measurements were recorded and stored to the ultrasound machine hard drive and within the ACERT 4.0 image archive and reporting system (CSC Group, Brecksville, OH). All MCA-PSV measurements were also recorded in a database specifically designed for the statistical analysis for this study.
Using a standard sample size formula for correlated data from Diggle et al6 a sample size of 50 women was deemed adequate.6 The outcome measures (MCA-PSV before and after vibroacoustic stimulation) were assumed to be normally distributed and z-test two-sample test was used for computing a sample size. The correlation of repeated measures over five examinations is assumed to be 0.75. Under two-tailed alpha=0.05, β=0.80, and the effect size of 0.5, we needed 50 women in each group. We anticipated 5% of women would not complete the study and 5% of women would deliver before 35 weeks of gestation, and thus they would not have all measurements performed. Therefore, we planned to enroll 60 women to achieve our desired sample size.
Linear mixed models7–9 were used first to investigate mean differences between MCA-PSV at basal fetal heart rate and after vibroacoustic stimulation at each examination; second, they were used to evaluate mean differences between fetal heart rate before and after vibroacoustic stimulation at each examination. A P<.05 was considered statistically significant for both fetal heart rate and MCA-PSV. All analyses were performed using SAS 8.0 statistical software (SAS Institute Inc., Cary, NC).
We enrolled 66 patients in the study. A total of 514 MCA-PSV measurements were obtained. These patients were part of a previous investigation to estimate the influence of angle correction on the MCA-PSV (Ruma MS, Swartz A, Kim E, Herring AH, Menard MK, Moise KJ. Angle correction can be used to measure peak systolic velocity in the fetal middle cerebral artery. Am J Obstet Gynecol. In press). All five monthly ultrasound examinations were completed for 50 fetuses (76%). Sixteen patients did not complete all five monthly ultrasound examinations during the study (Table 1). The most common reason for incomplete examinations was patient withdrawal from the study. One fetus during the study was diagnosed with a congenital cystic adenomatoid malformation, and this patient was excluded from the study. No fetus developed intrauterine growth restriction as assessed by serial ultrasound growth measures.
The mean±standard deviation gestational age for each of the five monthly ultrasound examinations was 18.5±1.7, 22.9±1.5, 27.1±1.3, 31.1±1.1, and 35.2±1.2 weeks, respectively. The mean basal fetal heart rate did not change significantly with advancing gestational age (P=.74). The mean change in fetal heart rate associated with vibroacoustic stimulation was dependent on gestational age, ranging from 1–21 beats per minute (bpm). Significant fetal heart rate increases were noted for examinations 3, 4, and 5 (P<.001 for all), with fetal heart rate increases of 8, 13, and 21 bpm, respectively (Fig. 1) (Table 2). After vibroacoustic stimulation, MCA-PSV measurements were significantly decreased compared with before vibroacoustic stimulation for examinations 3, 4, and 5 (P<.01, <.001 and <.001, respectively), with decrements of 3, 4, and 7 cm/s respectively. (Fig. 2) (Table 3).
Spontaneous decrease in the fetal heart rate not related to vibroacoustic stimulation was observed seven times during the course of the study. In three of these cases, the heart rate was sufficiently low to meet the definition of fetal bradycardia (79–90 bpm). The MCA-PSV measurement during these bradycardic episodes was twice that of the MCA-PSV during basal fetal heart rate (basal MCA-PSV 41.4 cm/sec; bradycardic MCA-PSV 80.2 cm/s). In the four remaining cases of decreased fetal heart rate after vibroacoustic stimulation, the mean fetal heart rate decrease was 5 bpm. An increase in the MCA-PSV of 3.2 cm/s was observed during these periods of decreased fetal heart rate. None of the bradycardia events were included in the main analysis. Middle cerebral artery peak systolic velocity measurements were reassessed when the fetal heart rate returned to a normal rate and the subsequent velocities were then included in the main analysis. No fetuses were found to be aneuploid or anomalous after delivery.
Evaluation of the fetal MCA-PSV by Doppler ultrasound has become the criterion standard of care in the screening and monitoring of fetal anemia. In the retrospective analysis of Mari et al4 a MCA-PSV of greater than 1.5 MoM was associated with a false-positive rate of 10% for the detection of moderate to severe anemia. Zimmerman et al10 undertook a prospective multicenter trial and reported a similar false-positive rate of 13%. Finally, Oepkes and coworkers11 noted a slightly higher false positivity of 18% for the detection of severe fetal anemia when the MCA-PSV was greater than 1.5 MoM. Based on the observations of Sallout et al4 we hypothesized that fetal heart rate accelerations were associated with an increase in the MCA-PSV. Measurements during periods of an active fetal behavioral state could account for the previously reported rates of a false-positive diagnosis of fetal anemia in association with an elevated MCA-PSV. However, our current investigation found the opposite to be true—fetal heart rate accelerations induced with vibroacoustic stimulation were associated with a decrease in the MCA-PSV.
The statistically significant increase in the fetal heart rate in response to vibroacoustic stimulation is similar to that reported by Kisilevsky et al.12 In that study, a maturation of the fetal heart rate response to vibroacoustic stimulation was noted with advancing gestational age at a threshold of 26 weeks of gestation. In our study, we did not detect a significant increase in heart rate until 27.1±1.3 weeks of gestation.
Other explanations must be sought for the inverse relationship between the MCA-PSV and fetal heart rate. An active fetal behavioral state is noted with advancing gestational age. It is defined as the presence of frequent accelerations of the fetal heart rate associated with fetal movement as well as increased baseline variability. In the only study to date that assessed the relationship between MCA-PSV and fetal behavioral state, an active fetal behavioral state was associated with an increased MCA-PSV.13 In that study, however, Shono and collegues13 found that the baseline fetal heart rate in the active state was not statistically different from the heart rate in the resting state. Additional MCA Doppler findings in the Shono cohort included an increase in the diastolic velocity, pulsatility index, and resistance index. These findings may represent a reduction in fetal cerebral vascular resistance in accordance with increased cerebral blood flow. In our study, an acute increase in fetal heart rate after vibroacoustic stimulation may be associated with an increase in fetal cardiac output. We conjecture that the fetal cerebral circulation reacts in a protective mechanism to prevent overdistension of the cerebral vessels. In these cases, one would expect a decrease in both the MCA-PSV as well as the pulsatility index due to an increase in cerebral resistance. Unfortunately, the latter characteristic was not measured in our current investigation to confirm this hypothesis. Another explanation for our findings might be related to decreased myocardial recovery time associated with increased fetal heart rate, resulting in decreased velocities. Indirect measures of myocardial recovery in utero may include total ejection isovolume index. A prospective study of the effects of increased fetal heart rate on the total ejection isovolume index may prove or disprove this hypothesis.
In conclusion, our data suggest that there is an inverse relationship between fetal heart rate and MCA-PSV. Assessment of the fetal heart rate should be conducted in concert with assessment of the MCA-PSV, particularly in the third trimester of pregnancy. Fetal heart rates above the basal heart rate during a spontaneous acceleration may contribute to a false-negative screen for fetal anemia. This finding may be particularly useful in situations where the MCA-PSV is borderline and approaching but below velocities of 1.5 MoM. As such, repeated MCA-PSV after accelerations have subsided my result in an elevated velocity above 1.5 MoM, indicating severe fetal anemia and making the patient a candidate for referral to a center where fetal transfusion therapy may be undertaken.
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© 2009 by The American College of Obstetricians and Gynecologists.
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