Time-interval changes of cardiac cycles in fetal growth restriction

European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 152–155

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Time-interval changes of cardiac cycles in fetal growth restriction Yasushi Kurihara a, Daisuke Tachibana a,*, Natsuko Yokoi a, Kayoko Nakagawa b, Kohei Kitada b, Masami Hayashi a, Sakika Yanai a, Hiroko Katayama a, Akihiro Hamuro a, Takuya Misugi a, Kazuharu Tanaka c, Mitsuru Fukui d, Masayasu Koyama a a

Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka, Japan Department of Obstetrics and Gynecology, Izumiotsu City Hospital, Osaka, Japan Department of Obstetrics and Gynecology, Osaka City General Hospital, Osaka, Japan d Laboratory of Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 February 2016 Received in revised form 25 April 2016 Accepted 21 May 2016

Objective: The aims of this study were to investigate the time intervals of each component of cardiac flow velocity waveforms (FVWs) in fetuses with fetal growth restriction (FGR) and to compare these with those of normal fetuses using reference ranges. Methods: The durations of atrioventricular (AV) valve opening (AVVO), AV valve closure (AVVC), total E(total-E) and A- (total-A) waves, total ejection time (total-ET), acceleration time (acc-E for E-wave, acc-A for A-wave, and acc-ET for ejection time), and deceleration time (dec-E for E-wave, dec-A for A-wave, and dec-ET for ejection time) were measured in fetuses with FGR. All variables were analyzed using z-scores. Results: Measurements of 17 growth-restricted fetuses were obtained. The time intervals between the last Doppler examination and delivery ranged from 0 to 6 days, with a median of 1 day. Significant increases were observed in AVVO, total-E, dec-E, and acc-A of the left heart. acc-E, acc-ET and AVVC of the left heart were significantly decreased. In the right heart, AVVO, total-E and dec-E were significantly increased. Conclusion: A prolonged time interval between early ventricular inflow and atrial contraction, as well as increased duration of AV valve opening, may reflect hemodynamic alterations in FGR fetuses. ß 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cardiac cycles Time-interval Fetal growth restriction Fetal circulation

Introduction Doppler assessment of the fetal circulation and cardiac function for the surveillance of fetal wellbeing is used clinically. Fetal growth restriction (FGR), which is one of the most challenging conditions in obstetrical management, needs to be assessed by sequential and detailed monitoring with Doppler methods, and the findings play a key role in perinatal decisions [1–4]. Using flow velocity waveforms (FVWs) obtained by Doppler methods, time-interval analysis has recently been introduced to examine fetal development and physiology. Nakagawa et al. showed that maturational changes appear in the time intervals of the fetal right heart, and the phenomena are reflected in those of the ductus venosus FVW [5]. These parameters were also found to

* Corresponding author at: Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi Abenoku, Osaka, Osaka 545-8585, Japan. Tel.:+81 6 6645 3862; fax: +81 6 6646 5800. E-mail address: [email protected] (D. Tachibana). http://dx.doi.org/10.1016/j.ejogrb.2016.05.044 0301-2115/ß 2016 Elsevier Ireland Ltd. All rights reserved.

show striking differences in the cases of recipients and donors of twin-to-twin transfusion syndrome [6]. Recently, we have constructed reference ranges of time intervals for mitral, tricuspid, aortic, and pulmonary FVWs, and characteristic differences between the right and left ventricles were seen in normal fetuses with progression of development and unequal blood volume owing to a unique shunt system [7]. The aims of this study were to investigate the time intervals of each component of cardiac FVWs in FGR fetuses and to compare them with those of normal fetuses using reference ranges.

Methods This is a descriptive study using prior established reference ranges [7]. Pregnancies with FGR (n = 19) were recruited at Osaka City University Hospital and Osaka City General Hospital from April 2010 to December 2015. A total of 9 of these cases have already been included in a previous study [8]. FGR was defined as an estimated fetal weight below 2.0 SDs with an elevated

Y. Kurihara et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 152–155

umbilical artery pulsatility index above the 95th percentile of the reference range [9,10]. Gestational age was calculated from the last menstrual period and confirmed by the crown-rump length at 9–11 gestational weeks. In the FGR group, only the last examination within one week before delivery was obtained retrospectively for analysis. The indication for delivery was nonreassuring fetal status or fetal demise. Exclusion criteria for both the reference and FGR groups were multiple pregnancies, chromosomal abnormalities, or structural anomalies. All participants gave their written, informed consent, and the study protocol was approved by the Institutional Review Board. Doppler studies were performed with Voluson E8 or E8 Expert (GE Healthcare, Milwaukee, WI, USA) ultrasound machines. All recordings were obtained in the absence of fetal breathing movements. The angle between the ultrasound beam and the direction of blood flow was less than 208. The fetal heart rate was within the normal range of 120–160 beats per minute with normal sinus rhythm, and the difference between each Doppler measurement was <5 beats per minute. The FVWs of right and left ventricular inflow were recorded from a four-chamber view of the fetal heart. The Doppler sample volume was placed slightly distal to the valve annulus between the tips of the leaflets [11]. The following time-related components were measured [7]: time interval from atrio-ventricular (AV) valve opening to valve closure (AVVO); time interval from AV valve closure to valve opening (AVVC); total duration of the E-wave (total-E); total duration of the A-wave (total-A); time from the opening of the AV valve to the peak of the E-wave (acc-E); time from the peak of the E-wave to the nadir between the E- and the A-waves (dec-E); time from the nadir between the E- and A-waves to the peak of the A-wave (acc-A); and time from the peak of the A-wave to the closure of the AV valve (dec-A) (Fig. 1). The following intervals were also defined in FVWs through the pulmonary and aortic valves: total ejection time (total-ET); time from the beginning of ventricular systole to peak velocity (acc-ET); and time from peak velocity to the end of ventricular systole (dec-ET) (Fig. 2). The Doppler echo of the opening of each valve (‘click’) was used as a landmark to optimize measurements of the limits of the ejection period [12]. Measurements were transformed into z-scores for comparison to reference ranges [13], according to the following formula: zscore = (XGA MGA)/SDGA, where XGA is the measured value at a known gestational age, MGA is the mean value according to the reference equation, and SDGA is the standard deviation associated with the mean value at this gestational age. Non-parametric tests (Mann–Whitney U-test and Wilcoxon signed-rank test) were used for comparisons of not normally distributed variables. P < 0.05 was regarded as significant. Results Of the 19 FGR cases, two were excluded; one had a ventricular septal defect that was diagnosed postnatally, and the other one showed fetal tachycardia. Measurements were obtained from the right and left cardiac cycle in all 17 growth restricted fetuses. In the FGR group, all cases except for two with fetal demise were delivered by caesarean section due to non-reassuring fetal status. The time intervals between the last Doppler examination and delivery ranged from 0 to 6 days, with a median of 1 day. Maternal and neonatal characteristics in FGR cases are shown in Table 1. All fetuses were severely restricted in growth. Table 2 shows z-scores of each variable in FGR cases. Significant increases were observed in AVVO, total-E, dec-E, and acc-A of the left heart. On the other hand, acc-E, acc-ET and AVVC of the left heart were significantly decreased. In the right heart, AVVO, total-E and dec-E were significantly increased.

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Fig. 1. Doppler tracing of the FVW of AV filling. (i) Duration of atrioventricular valve opening (AVVO), (ii) AV valve closing (AVVC), (iii) total duration of E-wave (total-E), (iv) time from opening of the AV valve to the peak of the E-wave (acc-E), (v) time from the peak of the E-wave to the nadir between the E- and A-waves (dec-E), (vi) total duration of the A-wave (total-A), (vii) time from the nadir between the Eand A-waves to the peak of the A-wave (acc-A), and (viii) time from the peak of the A-wave to closing of the AV valve (dec-A).

Discussion Applying the recently constructed reference ranges [7], this study demonstrated the characteristic changes of FVW timeintervals in FGR cases. In the left heart, increased opening duration of the mitral valve (Lt-AVVO) was observed with decreased closure duration (Lt-AVVC). In addition, these phenomena result from the increased duration of the early ventricular relaxation time (totalE), especially from its deceleration time (dec-E). Significant increase of tricuspid valve (Rt-AVVO) was also observed, possibly caused by increases of total-E and dec-E of right heart. Using other methods, Reed et al. measured human fetal tricuspid and mitral deceleration times in fetuses with growth restriction and the absence of end-diastolic Doppler velocities in the umbilical artery, and they found abnormally increased deceleration times across both ventricular valves in the FGR group [13]. Their results are partially in accordance with the present results, and the differences may be primarily due to methodological reasons, the number of cases, and the statistical methods. To overcome the fact that many of the time interval parameters are correlated with gestational age [7], the z-score was used to analyze the data, and significant increases were observed not only in the deceleration time of the E-wave, but also in the atrioventricular valve opening time. From the perspective of the phases of ductus venosus FVW, time interval differences between normal and FGR fetuses were demonstrated in our previous study, which suggests that time-interval alterations of the ductus venosus FVW, as well as cardiac cycles, may reflect the hemodynamic events caused by

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Y. Kurihara et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 203 (2016) 152–155 Table 2 The z-scores of each parameter in growth-restricted fetuses. Ventricle

AVVO

Right Left

0.26 0.30

0.08 0.20

1.12 1.12

0.048 0.036

total-E

Right Left

0.63 0.30

0.02 0.25

1.56 1.60

0.016 0.027

acc-E

Right Left

0.16 0.90

0.52 1.2

0.52 0.20

0.769 0.013

dec-E

Right Left

0.67 1.11

0.02 0.42

1.60 2.28

0.006 0.001

total-A

Right Left

0.14 0.36

0.40 0.20

0.64 0.64

0.817 0.354

acc-A

Right Left

0.38 0.74

0.07 0.40

0.64 1.48

0.182 0.047

dec-A

Right Left

0.27 0.20

0.68 0.60

0.60 0.15

0.662 0.334

AVVC

Right Left

0.79 0.96

1.53 1.80

0.38 0.30

0.050 0.002

total-ET

Right Left

0.10 0.50

0.66 0.99

0.42 0.41

0.551 0.207

acc-ET

Right Left

0.01 0.98

1.42 1.60

0.95 0.50

0.601 0.000

dec-ET

Right Left

0.30 0.69

1.04 0.90

0.76 1.06

0.873 0.242

*

Fig. 2. Doppler tracing of the FVW of ventricular outflow. (i) Total ejection time (total-ET), (ii) time from the beginning of ventricular systole to peak velocity (accET), and (iii) time from peak velocity to the end of ventricular systole (dec-ET).

placental insufficiency [8]. From another perspective, the fact that recipients in twin-to-twin transfusion syndrome show fused ventricular inflow patterns (monophasic patterns), especially through the tricuspid valve [14–16], may support the view that the changes in blood volume show the impacts on the timeintervals of valve motions, as well as intracardiac pressure. Moreover, studies of flow volume in the fetal heart reported that the ratio of right-sided to left-sided volume flow in FGR fetuses (2.15:1) was increased compared with values in normal fetuses (1.33:1) [17]. Considering this accumulated evidence, right predominance of the fetal heart, owing to the shunt system, may become more obvious in FGR, and this might in turn cause ‘relative’ or ‘functional’ hypovolemia in the left heart, resulting in changes in the cardiac cycles [8]. In fact, we have recently demonstrated that acute hemorrhage will cause striking increase of AVVO more in the left ventricle than in the right ventricle [18],

Table 1 Maternal and neonatal characteristics in the FGR group. FGR (n = 17) Age (years) Primiparous/multiparous Gestational age at measurement (weeks) GA at delivery (weeks) Birth weight (g) Apgar score (1 min) Apgar score (5 min) UA pH

29 (23–36) 15/2 28.7 (25.0–33.4) 29.0 (27.0–33.8) 693 (350–1281) 5 (1–9) 6 (2–9) 7.27 (7.07–7.32)

Data are given as medians (range). FGR, fetal growth restriction; GA, gestational age; UA, umbilical artery.

z-Score

First quartile

Third quartile

P value*

Parameter

P value was calculated compared with the normal reference ranges.

although the altered compliance should be further elucidated in both ventricles [19]. Rizzo et al. previously studied pulmonary and aortic time to peak velocity, which respectively correspond to right and left accET in the present study, and they observed decreased pulmonary time to peak velocity and increased time to peak velocity in FGR fetuses [20]. These observational discrepancies might be explained by the different intervals between the recordings and delivery (3 weeks and 1 day, Rizzo et al. and the present study, respectively). The afterloads of both ventricles might be substantially influenced by the vascular resistance of the two circuits, namely the placental and systemic circulation of the right ventricle and the upper body (mainly cerebral circulation) of the left ventricle, and these afterloads are altered by the progression of the disease [21]. Indeed, the compensatory mechanism of cerebral vasodilation may be lost when there is severe hypoxemia or development of brain edema [22]. An altered direction of blood flow at the level of the aortic isthmus may also complicate this phenomenon [23–25]. As such, it is not possible to differentiate which is a cause or a secondary consequence among the various concomitant factors. The limitations of the present study are the relatively small number of FGR cases and the lack of comparisons with other variables, such as cardiac output. Associations with the exact sequence of events (i.e. severity of umbilical arterial flow, dilatation of cerebral artery, right-left cardiac output, etc.) also remain to be elucidated. In conclusion, this is the first report to show the prolonged time intervals between early ventricular inflow and atrial contraction, as well as increased durations of AV valve opening in FGR fetuses. These findings may reflect the pathophysiological circulation in growth-restricted fetuses, providing the additional insights to the previous studies [19,26,27]. Further studies are needed to compare these new parameters and other indices in the field of fetal wellbeing surveillance.

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