Background
Phase-rectified signal averaging, an innovative signal processing technique, can be used to investigate quasi-periodic oscillations in noisy, nonstationary signals that are obtained from fetal heart rate. Phase-rectified signal averaging is currently the best method to predict survival after myocardial infarction in adult cardiology. Application of this method to fetal medicine has established significantly better identification than with short-term variation by computerized cardiotocography of growth-restricted fetuses.
Objective
The aim of this study was to determine the longitudinal progression of phase-rectified signal averaging indices in severely growth-restricted human fetuses and the prognostic accuracy of the technique in relation to perinatal and neurologic outcome.
Study Design
Raw data from cardiotocography monitoring of 279 human fetuses were obtained from 8 centers that took part in the multicenter European “TRUFFLE” trial on optimal timing of delivery in fetal growth restriction. Average acceleration and deceleration capacities were calculated by phase-rectified signal averaging to establish progression from 5 days to 1 day before delivery and were compared with short-term variation progression. The receiver operating characteristic curves of average acceleration and deceleration capacities and short-term variation were calculated and compared between techniques for short- and intermediate-term outcome.
Results
Average acceleration and deceleration capacities and short-term variation showed a progressive decrease in their diagnostic indices of fetal health from the first examination 5 days before delivery to 1 day before delivery. However, this decrease was significant 3 days before delivery for average acceleration and deceleration capacities, but 2 days before delivery for short-term variation. Compared with analysis of changes in short-term variation, analysis of (delta) average acceleration and deceleration capacities better predicted values of Apgar scores <7 and antenatal death (area under the curve for prediction of antenatal death: delta average acceleration capacity, 0.62 [confidence interval, 0.19–1.0]; delta short-term variation, 0.54 [confidence interval, 0.13–0.97]; P =.006; area under the curve for prediction Apgar <7: average deceleration capacity <24 hours before delivery, 0.64 [confidence interval, 0.52–0.76]; short-term variation <24 hours before delivery, 0.53 [confidence interval, 0.40–0.65]; P =.015). Neither phase-rectified signal averaging indices nor short-term variation showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85).
Conclusion
The phase-rectified signal averaging method seems to be at least as good as short-term variation to monitor progressive deterioration of severely growth-restricted fetuses. Our findings suggest that for short-term outcomes such as Apgar score, phase-rectified signal averaging indices could be an even better test than short-term variation. Overall, our findings confirm the possible value of prospective trials based on phase-rectified signal averaging indices of autonomic nervous system of severely growth-restricted fetuses.
The variability in heart rate is determined by several mechanisms that include opposing sympathetic and vagal influences of the autonomic nervous system (ANS) in addition to respiratory, baroreflex, and circadian processes. Its analysis has long been established as a useful predictor of cardiovascular health in the fetal, newborn, and adult periods. Human fetuses that are affected with severe growth restriction show a decrease in fetal heart rate (FHR) variability. Short-term variation (STV), which is a calculated measure that was designed to make an assessment of FHR variability quantitative, has proved to be predictive of fetal distress in the antenatal setting. Values for STV of <2.6 milliseconds are known to be associated highly with fetal metabolic acidemia (defined as umbilical artery base deficit of >12 mmol/L) and/or intrauterine death, whereas STV values of >3 milliseconds rarely are associated with adverse outcome.
In contrast to other methods of analysis of FHR variability, phase-rectified signal averaging (PRSA) permits the detection of quasi-periodicities in nonstationary, noisy variables, which are typical signals that are represented by the heart rate, thereby allowing complex oscillatory modulations of multiple frequency drivers to be determined, rather than simply describing the degree of variability from the baseline. PRSA predicts survival after myocardial infarction in adult cardiology and has been investigated successfully in fetal medicine, despite the challenges of a nonstationary signal, with more interference in the signal obtained than in the adult after the infarction. PRSA, in short, calculates not only the variation of the FHR, but also the speed of changes in FHR, which are described as the average acceleration (AAC) and deceleration (ADC) capacities. The novel parameter AAC better differentiates growth-restricted fetuses from control fetuses than analysis by STV. Accurate prediction of fetal growth restriction by PRSA analysis has also been confirmed by investigators who compared data from both Doppler imaging and transabdominal fetal electrocardiogram signals.
Even acute intrapartum hypoxia might be better predicted with the use of PRSA than STV analysis. Therefore, analysis of alterations in FHR by PRSA holds potential in predictive value of acute and chronic fetal hypoxia in complicated pregnancy. However, this has not been tested systematically in large cohorts.
The most comprehensive, multicenter study of human early fetal growth restriction is the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE). In TRUFFLE, >500 pregnancies were monitored for fetal health surveillance with the use of Doppler indices in the ductus venosus or STV that was determined by computerized cardiotocography (c-CTG). Perinatal outcome and intermediate neurologic outcome at 2 years of age were also determined. The aim of this study was to apply PRSA analysis to FHR data that were obtained from the TRUFFLE cohort to compare, for the first time, the longitudinal changes of PRSA and STV and the prognostic value for the prediction of adverse perinatal and neurologic outcome in severely growth-restricted human fetuses.
Materials and Methods
The TRUFFLE clinical trial was a prospective, multicenter randomized study performed in 5 European countries and 20 tertiary care centers. Women were eligible for inclusion if they had a singleton pregnancy between 26 and 31+6 weeks of gestation that was affected by fetal growth restriction , which was defined as a fetal abdominal circumference <10th percentile and abnormal umbilical artery Doppler with a pulsatility index >95th percentile. Exclusion criteria were ultrasound appearances that were suggestive of congenital fetal abnormality, abnormal karyotype on invasive testing, or women <18 years of age. The study protocol was approved by the institutional ethics committee, and patients provided written informed consent. Participants were assigned randomly to 1 of 3 groups (c-CTG STV reduction and early or late ductus venous changes) to establish the timing of delivery. Baseline maternal and fetal characteristics were collected at study entry.
In the CTG randomization arm, the timing of delivery was decided on the following cut-off values: STV <3.5 milliseconds at <29 weeks of gestation or STV <4 milliseconds at ≥29 weeks of gestation. In cases in which maternal corticosteroids were given to accelerate fetal lung maturation, no decision regarding delivery was made on the grounds of reduced STV up to 72 hours after the first intramuscular dose, because maternal corticosteroids are known to produce short-term reductions in FHR variability. Monitoring in all 3 groups included umbilical artery Doppler imaging, and c-CTG was recommended at least once a week. However, most centers performed c-CTGs more frequently, subject to local policies. “Safety net” criteria, which prompted delivery regardless of any other measures, included spontaneous FHR decelerations or a STV <2.6 milliseconds at 26+0 to 28+6 weeks of gestation or STV <3 milliseconds at ≥29 weeks of gestation. Furthermore, delivery was recommended if reversed umbilical artery end diastolic flow occurred at ≥30 weeks of gestation or if there was absent umbilical artery end diastolic flow at ≥32 weeks gestation. Further details about the study protocol can be obtained from the original publication.
All participating centers were invited to provide c-CTG raw data for this secondary analysis, and all registrations that were available in the 5 days preceding delivery or antenatal fetal death were selected for inclusion. Therefore, 4 time windows were selected. From all participating centers, 8 of 20 were able to provide appropriate c-CTG raw data (Amsterdam, Brescia, Hamburg, London, Munich, Naples, Rotterdam, and Zwolle). The complete c-CTG signal was used for analysis. According to protocol c-CTGs were recorded with the Sonicaid System 8002 (Oxford Instruments Medical Ltd, Surrey, UK). Data were analyzed directly for STV with the use of the original Dawes/Redman algorithm and by the PRSA method for AAC and ADC calculation, which was described in detail by Lobmaier et al. For PRSA, data were analyzed off-line after computer download, and the following parameters were used: T=10 samples, L=100 samples; anchor points were defined as increases (AAC) or decreases (ADC) of <5%. CTG data do not reflect real beat-to-beat heart rates. CTG technique works with a frequency of 4 Hz. That means that, 4 times per second, the FHR is detected so that the filter of T=10 samples corresponds to 2.5 seconds, and T = 10 samples and L = 100 samples corresponds to 25 seconds. Not all centers had a computer connected to the CTG device. That is the reason for missing CTG raw data from the centers that did not provide data.
Delta (Δ) values of AAC, ADC, and STV were calculated, taking the difference between the first (5–4 days before delivery) and last (<24 hours before delivery) values before delivery or intrauterine fetal death.
Statistical analysis was performed with SPSS for Windows (version 22.0; SPSS Inc, Chicago, IL) and R (version 3.2.2; R Core Team [2015]. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at: https://www.R-project.org/ ). For comparison of mean values at different time points, an analysis of variance for repeated measurements was performed. If a significant change of mean values was observed over time in the analysis of variance, the Student t test for paired data was used for comparison of consecutive time points and for a comparison of the first (5–4 days before delivery) to the last (within 24 hours before delivery) measurement. The diagnostic effectiveness of the different c-CTG parameters for outcome prediction was analyzed with the use of the area under the receiver operating characteristic (ROC) curve (AUC). Confidence intervals for the AUCs were estimated based on 2000 bootstrap samples each. Comparisons between AUCs was performed with the test proposed by Hanley and McNeil, with standard deviation of the difference between the AUCs estimated from 2000 bootstrap samples. Therefore, the function roc.test that is provided in the R library pROC was used. All statistical comparisons were conducted 2-sided, and a probably value of <.05 was considered statistically significant.
Results
A total of 279 fetuses and 947 c-CTG records (3.4 CTG records per fetus) were available for secondary analysis for this study. From 1 center (Rotterdam), STV data could not be extracted for technical reasons so that only PRSA indices were available for Rotterdam patients. Data for the study population demographic characteristics and obstetric and neonatal outcomes are summarized in Table 1 . Considering adverse outcomes, 11.1% of the neonates had a 5- minute Apgar <7, and 3.2% of neonates had an umbilical artery pH of <7.1, suggestive of poor condition at birth in these infants. A Bayley score developmental quotient of <95 was observed in 22.9% neonates, and a score of <85 in 5.0% at the 2-year follow up was suggestive of moderate developmental disability in these infants.
| Variables | Total (n=279) |
|---|---|
| Demographic and clinical characteristics | |
| Mean maternal age, y±SD | 30.5±5.6 |
| White ethnicity, n (%) | 221 (79.2) |
| Nulliparous, n (%) | 174 (62.4) |
| Mean body mass index, kg/m 2 ±SD | 25.4±6.0 |
| Smoking, n (%) | 50 (17.9) |
| Diabetes mellitus, n (%) | 2 (0.7) |
| Chronic hypertension, n (%) | 28 (10.0) |
| Renal morbidity, n (%) | 5 (1.8) |
| Other medical disease, n (%) | 46 (16.5) |
| Any gestational hypertensive disease, n (%) | 53 (19.0) |
| Preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), n (%) | 122 (43.7) |
| Mean gestational age at entry, wk±SD | 29.1±10.5 |
| Mean estimated fetal weight by ultrasound imaging, g±SD | 886.2±210.1 |
| Mean umbilical artery pulsatility index, ±SD | 2.01±0.58 |
| Umbilical artery absent or reversed end diastolic flow, n (%) | 111 (39.8) |
| Mean umbilical artery pulsatility index to median cerebral artery pulsatility index ratio, ±SD | 1.48±0.61 |
| Mean ductus venosus pulsatility index, ±SD | 0.60±0.02 |
| Obstetric outcome | |
| Mean gestational age at delivery, wk±SD | 30.6±2.0 |
| Mean interval to delivery, d±SD | 10.2±10.2 |
| Cesarean delivery, n (%) | 272 (97.5) |
| Mean birthweight, g±SD | 1000.8±280.9 |
| Male sex, n (%) | 137 (49.1) |
| Apgar score <7 | 31 (11.1) |
| Umbilical artery pH | |
| Data available, n (%) | 202 (72.4) |
| Mean pH±SD | 7.26±0.08 |
| <7.0, n (%) | 4 (1.4) |
| <7.1, n (%) | 9 (3.2) |
| Neonatal outcome, n (%) | |
| Live birth | 255 (91.4) |
| Neonatal death | 18 (6.4) |
| Antenatal death | 6 (2.2) |
| Bayley III test performed | 219 (78.5) |
| Developmental quotient | |
| <85 | 14 (5.0) |
| <95 | 60 (22.9) |
Mean values of AAC, ADC, and STV at 4 different time points (5-4 days before delivery, at 72–48 hours, at 48–24 hours, <24 hours) were calculated and compared ( Figure ). At 5–4 days compared with <24 hours before delivery AAC was reduced from 1.97±0.39 (SD) to 1.69±0.45, ADC from 1.95±0.40 to 1.69±0.48, and STV from 6.07±2.14 to 4.71±2.14. Although a progressive decrease in all 3 indices of fetal health was obtained towards delivery, the decrease for AAC and ADC became significant 72 hours before performed delivery; the decrease in STV became statistically significant at <48 hours before delivery.
The AUC value was calculated for each main perinatal outcome. Table 2 shows the results of the ROC curve comparisons considering the delta values for each variable between the 5–4 days to 24 hours before delivery time interval or using the last index within 24 hours before delivery. Although changes in AAC and ADC showed a general trend towards better predictive performance for adverse outcomes than STV, this was significant only for ΔAAC in the prediction of antenatal death and for ADC in the 24 hours before delivery to predict an Apgar score <7. Neither ΔAAC, ΔADC, or ΔSTV or AAC, ADC, or STV in the last 24 hours before delivery showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85).
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