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Cardiovascular Research 1998 37(3):601-605; doi:10.1016/S0008-6363(97)00235-6
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

An estimate of fetal autonomic state by spectral analysis of human umbilical artery flow velocity waveforms

Nicolette T.C Ursema, Mark H Kempskib, Maria A.J de Ridderc, Edward B Clarkd and Juriy W Wladimiroffa,*

aDepartment of Obstetrics and Gynecology, Academic Hospital Rotterdam — Dijkzigt, Erasmus University, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands
bDepartment of Mechanical Engineering, Rochester Institute of Technology, Rochester, NY, USA
cInstitute of Epidemiology and Biostatistics, Erasmus University, Rotterdam, Netherlands
dSCOR in Pediatric Cardiovascular Diseases, Division of Pediatric Cardiology, University of Rochester Medical Center, Rochester, NY, USA

* Corresponding author. Tel. (+31-10) 463 3632; Fax (+31-10) 463 5826.

Received 19 June 1997; accepted 5 September 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Determination of gestational age-related fluctuations in heart rate in the umbilical artery of the early human fetus. Methods: Doppler velocity recordings from human umbilical artery were obtained, in a cross-sectional study design in 137 singleton pregnancies at 10–20 weeks of gestation. After exclusion criteria were applied, data on 117 normal pregnancies were available and subdivided into group I: 10–12 weeks (n=49); group II: 13–16 weeks (n=43); and group III: 17–20 weeks (n=25). Blood flow velocity waveforms were reconstructed from Doppler audio signals. Variability in heart rate was calculated using Fast Fourier Transforms (FFT). Individual heart rate variability power spectra were subdivided into frequency bands. Results: Fetal heart rate variability decreases at 10–20 weeks and demonstrates a shift to lower frequencies at 17–20 weeks. Conclusions: Fetal heart rate variability is related to gestational age and shows a shift to lower frequencies which may reflect autonomic functional development.

KEYWORDS Umbilical artery velocimetry; Human; Fetal heart rate; Autonomic nervous system


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The analysis of variations in cardiovascular parameters is an established non-invasive technique for investigating the autonomic control of the cardiovascular system. In man, heart rate variability estimated by spectral analysis reflects the activity of parasympathetic and sympathetic limbs of the autonomic nervous system [1–3]. Long and short term variations in heart rate differ with advancing gestational age and through early postnatal life coincident with maturation of the autonomic nervous system [3, 4]. However, the analysis of heart rate variability during the development of autonomic innervation has remained limited.

In the preinnervated chick embryo, heart rate variability and blood flow velocity variability will likely indicate variations in cardiovascular output related to function, growth and morphogenesis [5, 6].

We are pioneering the application of these principles in early human fetal development. Using combined transvaginal and transabdominal Doppler ultrasonography, it is now feasible to measure human fetal arterial and venous flow velocities during the late first and early second trimesters of pregnancy [7]. Digital signal processing of these fetal flow velocity waveforms allowed the definition of flow velocity and heart rate variability. The objective of the present study was to determine the relationship between gestational age and fluctuations in heart rate in the umbilical artery of the normal human fetus at 10–20 weeks of gestation.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
A total of 137 women with a normal singleton pregnancy between 10–20 weeks of gestation (median 15 weeks) consented to participate in the study. Maternal age ranged from 14 to 46 years (median 28 years). Pregnancy duration was determined from the last menstrual period and confirmed by ultrasound measurement of fetal crown-rump length (10–12 weeks) or fetal biparietal diameter (13–20 weeks). Three different gestational age groups were enrolled into the study, group I: 10–12 weeks (n=49), group II: 13–16 weeks (n=43), and group III: 17–20 weeks (n=25). The study protocol was approved by the institutional review boards at the Erasmus University, Rotterdam, and both the Rochester Institute of Technology and the University of Rochester, Rochester, NY. Each woman was included in the study only once. Only pregnancies which progressed uneventfully resulting in the delivery of a normal infant with a birth weight between the 10th and 90th percentile corrected for maternal parity and fetal sex [8]were included in the data analysis.

2.2 Doppler recordings
Pulsed wave Doppler ultrasound recordings were obtained using a Toshiba SHH-140A (Toshiba Corporation, Medical Systems Division, Tokyo, Japan). A combined transvaginal real-time and pulsed Doppler system (carrier frequency 6 MHz and 5 MHz, respectively) was used at 10–13 weeks of gestation and a combined transabdominal real-time and pulsed Doppler system (carrier frequency 5 MHz and 3.75 MHz, respectively) was used at 14–20 weeks of gestation. The system operates at power outputs of less than 100 mW/cm2 spatial peak-temporal average in both imaging and Doppler modes by manufacturer's specifications. The angle of insonation was always less than 30 degrees. Sample volume length for all flow velocity waveforms ranged between 0.2 and 0.3 cm; the high-pass wall filter was set at 70–100 Hz. Doppler recordings were performed by one examiner (NTCU). All Doppler studies were carried-out with the women lying in a semirecumbent position and during fetal apnea. Maximal flow velocity waveforms from the umbilical artery were obtained from a floating loop of the umbilical cord. Only technically high quality recordings lasting more than 16 s, and therefore containing at least 40 peak flow velocity waveforms, were analyzed. This was to ensure an adequate collection of waveforms for the heart rate variability analysis. The velocity waveforms (video and Hi-Fi audio signal) were stored on sVHS video tape in PAL format using a Panasonic model AG7350 machine (Matsushita Electric, Japan).

2.3 Data analysis
Continuous high quality Doppler audio waveforms were digitized at 44 kHz for greater than 16 s intervals using an analog-to-digital data acquisition board (LabPC+ and BNC-2081 boards, National Instruments, Austin, TX). Flow velocity waveforms were reconstructed from the Doppler audio data using the ‘DopV’ collection of computer algorithms developed at the Rochester Institute of Technology using LabVIEW software (National Instruments, Austin, TX). We determined mean velocity (mm/s), and instantaneous heart rate (bpm) for each cardiac cycle. To measure instantaneous (i.e. beat-to-beat) heart rate, we used a global mean velocity threshold detection scheme. When the rising edge of the velocity signal crossed the threshold, an event marker was set (Fig. 1). Instantaneous heart rate was determined from the reciprocal of the difference in successive threshold event times. Global mean heart rate was calculated by taking the average of the respective pulsatile values over the entire velocity series. Heart rate variability time series were calculated by using a piece-wise linear interpolation of the heart rate beat series. To remove the DC-drift we used a second-order polynomial fit. After quadratic de-trending, the heart rate time series were passed through a 5th order Butterworth low pass filter, with a cut-off frequency of 4 Hz. To compute the power spectral density of each variability time series, we used Fast Fourier Transforms. Power spectral density identifies the frequency–domain heart rate characteristics. For comparison, the individual heart rate variability power spectra were subdivided into 10 frequency bands of 0.15 Hz width, covering the range from 0 to 1.5 Hz. Spectral power was expressed as the absolute band power values as well as the total power between 0 and 1.5 Hz. Total heart rate variability is equated to the total power (i.e. area under the curve) in the spectrum of the heart rate. The band powers were computed from the respective spectra in each pre-defined band and for the entire spectrum under consideration. The band power and total power for respective fetuses were then averaged across each gestational age group.


Figure 1
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  		Fig. 1 Schematic reconstruction of umbilical artery flow velocity waveforms with indicators for peak velocity (crosses), mean velocity (triangles) and threshold value (circles).

 
2.4 Statistical analysis
All data are presented as mean±s.e.m. or as mean and 95% confidence interval. A logarithmic transformation of some variables was performed to obtain normal distributions. For statistical comparison of the three study groups, we selected an analysis of variance (ANOVA). If the result was significant (p<0.05) pairwise comparisons with a Student–Newman–Keuls correction were performed. Medians, percentiles (25th and 75th), and interquartile ranges were used to describe the characteristics of the heart rate variability frequency distribution. Statistical significance was defined by a value of p<0.05. Calculations were performed with SPSS 6.1 software (SPSS, Chicago, IL).


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
Of the 137 women who consented to participate in the study, seven women were excluded independently of the study protocol because of a fetal birth weight below the 10th percentile or above the 90th percentile for gestational age and 13 women were excluded because of pregnancy pathology, such as gestational hypertension and premature labor later in gestation. Flow velocity waveforms recordings from 117 fetuses were available for further analysis.

Global mean heart rate decreased (p<0.05) and global mean flow velocity increased (p<0.05) with advancing gestational age (Table 1). An example of the heart rate time series and their power spectra from each of the age groups is depicted in Fig. 2.


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  		Table 1 Fetal global mean heart rate and global mean flow velocity

 

Figure 2
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  		Fig. 2 Examples of heart rate times series and their spectra (A–C). Group I: 10–12 weeks (A), group II: 13–16 weeks (B), and group III: 17–20 weeks (C).

 
Total heart rate variability decreased with gestational age from 10 to 20 weeks (Table 2). Total heart rate variability in group I was twice that in group III. Fig. 3 demonstrates that the band power distribution of heart rate variability decreased in amplitude with gestational age above 0.3 Hz. Below frequency 0.3 Hz, heart rate variability was similar among the three gestational age groups (Fig. 3, Table 3). Analysis of heart rate variability distribution demonstrated that median and percentiles decreased with gestational age, indicating that later in pregnancy heart rate variability is centered around lower frequencies (Table 2).


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  		Table 2 Descriptive statistics of heart rate variability band power distribution

 

Figure 3
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  		Fig. 3 Heart rate variability band power spectra for gestational age groups; I: 10–12 weeks, II: 13–16 weeks, and III: 17–20 weeks. Data are presented as mean±s.e.m.

 

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  		Table 3 Summary of analysis of variance of the heart rate variability band power spectrum

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
During the last 15 years, there has been an increasing interest in cardiovascular beat-to-beat variations generated by the autonomic nervous system. Studies investigating heart rate variability in adults indicate the influence of three oscillating physiologic mechanisms arising from respiration, baroreceptor activity, and vasomotor activity [1, 9].

Although data from late gestation fetal heart rate variability are available, there are still many questions regarding the normal heart rate variability spectrum. Frequency analysis of heart rate in humans of all ages has revealed two prominent frequencies of variation: the high-frequency band (0.15–0.45 Hz) which is controlled by parasympathetic tone and the low-frequency band (0.03–0.15 Hz) which is controlled by sympathetic tone [10–12]. Fluctuations in heart rate variability in premature and full-term neonates indicate post-term maturation of the autonomic nervous system [13, 14]. Long and short term variability in fetal heart rate was studied on the basis of previous findings in the instrumented chick embryo [5, 6]which focused on flow velocity and heart rate variability. In our study we discarded the power spectra frequency band, 0–0.15 Hz, since the Doppler signal duration (>16 s) was too short for reliable interpretation of frequencies below 0.15 Hz.

Animal studies done in the developing heart have demonstrated that autonomic nerves reach the heart in the late embryonic period [15]. Histological and ultrastructural studies have shown the presence of developing nerves in the human heart at 5–6 weeks of gestation [16]. The ontogenesis of parasympathetic cardiac innervation is considered to precede that of sympathetic innervation in chick and most mammals including man [17]. In the early developing heart, the presence of intracardiac nerves may not reflect functional innervation [17, 18]. Walker [19]showed in vitro evidence for the possibility of autonomic neuroeffector transmission in the human fetus at 16–17 weeks of gestation, yet there is no evidence of reflex activation of the autonomic nervous system by respiration, baroreceptors or vasomotor activity.

In the present study, we observed a random broad band pattern of heart rate variability in group I and group II (Fig. 3), which may indicate that the autonomic control mechanisms are not yet developed. Karin et al. [3]demonstrated that at 23 weeks of gestation, the functionally immature fetal autonomic nervous system generates a large variability in heart rate, resulting in a power spectrum with twice as much energy, when compared with the more mature and more stable autonomic nervous system during the last period of gestation (40 weeks). In the present study, gestational age group III (17–20 weeks) presents a further decrease in fetal heart rate variability which is centered around lower frequencies compared to group I and II (Table 2). This may reflect some degree of autonomic function during this period of fetal life.

In adults, the heart rate power spectrum reveals a clear peak in the higher frequency range, which is attributed to breathing activity. In the fetus, a widely dispersed respiration peak is observed around the 0.7 Hz center, although not as powerful and focused as in adults [3]. The heart rate band power spectrum in our study also displayed high frequency variability. Whilst fetal breathing movements may occur as early as 11 weeks of gestation [20], this high frequency component does not represent fetal breathing activity, since all our Doppler recording were performed during fetal apnea.

It can be concluded that the data presented reflect normal fetal heart rate variability which is characterized by a decrease with advancing gestational age and a shift to lower frequencies at 17–20 weeks suggesting autonomic functional development.

Time for primary review 21 days.


   Acknowledgements
 
This study was supported by National Institute of Health Grant P50-HL51498, SCOR in Pediatric Cardiovascular Disease, at the University of Rochester, Rochester, NY. The authors wish to thank Dr. F.K. Lotgering, Department of Obstetrics and Gynecology at Academic Hospital Rotterdam — Dijkzigt and Dr. B.B. Keller, Department of Pediatrics at the University of Rochester for their helpful comments.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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