Comparison of alterations in fetal regional arterial vascular resistance in appropriate-for-gestational-age singleton, twin and triplet pregnancies

Masashi Akiyama1, Atsushi Kuno, Yasuko Tanaka, Hirokazu Tanaka, Keiji Hayashi, Toshihiro Yanagihara and Toshiyuki Hata

Department of Perinatology, Kagawa Medical University, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The objective of this longitudinal study was to evaluate alterations in fetal vascular resistance of fetal peripheral arteries with advancing gestation in singleton appropriate-for-gestational-age (S-AGA), twin appropriate-for-gestational-age (Tw-AGA) and triplet appropriate-for-gestational-age (Tri-AGA) infants. Colour Doppler flow imaging and pulsed Doppler ultrasonographic examinations were performed on 35 S-AGA, 52 Tw-AGA and 12 Tri-AGA fetuses. The pulsatility index for middle cerebral artery (MCAPI), umbilical artery (UAPI), descending aorta (DAPI), splenic artery (SAPI), renal artery (RAPI) and femoral artery (FAPI) was measured as vascular resistance every 2 weeks after 15 weeks of menstrual age until delivery. Optimal models and normal ranges for pulsatility index for each artery in each group were generated. The alterations in various fetal regional arterial pulsatility indices with advancing gestational age showed no significant differences in S-AGA, Tw-AGA and Tri-AGA infants, respectively. These results suggest that there is no significant difference for regional arterial vascular resistance in AGA fetuses among singleton, twin, and triplet pregnancies, whereas there was a slight difference in fetal growth pattern among singleton, twin, and triplet pregnancies described in our previous investigation.

Key words: appropriate-for-gestational-age fetus/Doppler ultrasound/fetal artery/multiple pregnancy/pulsatility index/singleton pregnancy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
With the introduction of ovulation-inducing agents, the incidence of multiple pregnancies has increased (Holcberg et al., 1982Go; Loucopoulos and Jewelewicz, 1982Go). Moreover, the implementation of multiple embryo transfer in in-vitro fertilization (IVF) programmes may further increase multiple pregnancies (Weissman et al., 1990Go). Multiple pregnancies are known to be at increased risk of a variety of complications during the antepartum and intrapartum periods (Landy and Keith, 1998Go). These complications include premature delivery, fetal growth restriction, congenital anomalies, placenta praevia, placental abruption, cord accidents, and malpresentations. Due to the complexity of multiple pregnancies, obstetric management is more difficult, and thus a means for evaluating its effectiveness is essential (Xu et al., 1995Go).

It has been suggested (Hata et al., 1991Go; Xu et al., 1995Go) that the deposition of soft tissue seen in normal singletons during the third trimester occurs to a much lesser extent in normal twins and triplets. Kuno et al. (1999) gave strong support to these works (Hata et al., 1991Go; Xu et al., 1995Go). Therefore, further study is needed to clarify whether this decrease in soft tissue deposition in multiple pregnancies represents a true growth abnormality or merely a physiological adaptation to the energy demands associated with the support of growth in multiple fetuses.

With recent advances in Doppler ultrasound, especially in colour Doppler flow imaging, various fetal vessels have been investigated (Arduini and Rizzo, 1990Go; Manabe et al., 1995Go). The use of a sensitive colour flow Doppler apparatus to identify and reliably insonate specific small diameter vessels has greatly facilitated the study of the blood flow within individual fetal organs (Belfort et al., 1993Go). However, most fetal Doppler studies were done in singleton pregnancies, and there have been a few reports on fetal Doppler velocimetry in multiple pregnancies (Nimrod et al., 1987Go; Giles et al., 1990Go; Gaziano et al., 1991Go; Degani et al., 1992Go). Moreover, to date, there has been no known report on fetal peripheral arterial Doppler velocimetry, such as splenic artery, renal artery, and femoral artery, in multiple pregnancies.

The objective of the present study was to construct reference limits for pulsatility index (PI) values from middle cerebral artery (MCA), descending aorta (DA), splenic artery (SA), renal artery (RA), femoral artery (FA), and umbilical artery (UA), based on a longitudinal study of 35 singleton appropriate-for-gestational-age (S-AGA), 52 twin appropriate-for-gestational-age (Tw-AGA), and 12 triplet appropriate-for-gestational-age (Tri-AGA) infants, and to evaluate the alterations in those PI values among these three groups during gestation.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Thirty-five S-AGA (18 females and 17 males), 52 Tw-AGA (27 females and 25 males) in 28 pregnancies (nine monochorionic diamniotic and 19 dichorionic pairs), and 12 Tri-AGA (eight females and four males) in five pregnancies (five trichorionic triplets) were studied. Four twins (two small-for-gestational-age and two large-or-gestational-age infants) and three triplets (two small-for-gestational-age and one large-for-gestational-age infants) were excluded from the study. One S-AGA pregnancy was excluded from the study due to the appearance of maternal systemic lupus erythematosus during pregnancy, and one S-SGA pregnancy due to fetal abnormalities. All fetuses were part of our previous study on fetal growth and fetal organ growth in multiple pregnancies (Kuno et al., 1999Go). All the pregnancies were in middle-class Japanese women from Kagawa area. All women were non-smokers, with neither indication of maternal complication nor evidence of drug ingestion. All the obstetric deliveries were made in our university hospital, and comprehensive paediatric assessment (within 24 h of delivery) revealed no evidence of genetic diseases or congenital anomalies. There were nine monochorionic diamniotic and 16 dichorionic pairs that were conceived naturally. Two pregnancies were induced artificially, one by induction of ovulation and one by IVF, in the Tw-AGA group. All five pregnancies were IVF pregnancies in the Tri-AGA group. The study was approved by the local ethical committee of Kagawa Medical University, and standardized informed consent was obtained from each patient.

Fetal age determination was estimated from the first day of the last menstrual period and confirmed by the first-trimester and early second-trimester ultrasound examinations (crown–rump length, biparietal diameter, and femur diaphysis length measurements) (Tsuzaki et al., 1982Go; Iwamoto, 1983Go) or determined from the date of conception (IVF pregnancies) plus 2 weeks (the ultrasound age estimates confirmed these age determinations).

Ultrasound examinations were carried out at 2 week intervals beginning at ~15 weeks of menstrual age continuing until delivery. The number of examinations of individual patients ranged (mean ± SD) from 5 to 13 (9.3 ± 2.1) in the S-AGA group, from 5 to 12 (8.0 ± 2.0) in Tw-AGA group, and from 8 to 10 (9.5 ± 0.9) in the Tri-AGA group. At each examination, each fetus was identified by its position in the uterus, its size, or its sex in multiple pregnancies. Measurements of the biparietal diameter, head circumference, abdominal circumference and femur diaphysis length were obtained at each examination for each fetus using procedures described in a previous publication (Deter et al., 1981Go). The estimated weight was determined from values for the biparietal diameter, abdominal circumference, and femur diaphysis length as described previously (Shinozuka et al., 1987Go).

Results are expressed as mean ± SD. Statistical analysis for comparison of maternal age, parity, and Apgar score among the groups was done using a Kruskal–Wallis one-way analysis of variance. Maternal height, maternal weight, birth age, birth weight, neonatal crown–heel length, neonatal head circumference, neonatal abdominal circumference, and neonatal thigh circumference were compared using an analysis of variance (ANOVA) and Neuman–Keuls multiple comparison test. P < 0.05 was considered to be significant.

Colour Doppler flow imaging and pulsed Doppler ultrasonography with a 3.5 MHz convex transducer (Aloka SSD-2000, Tokyo, Japan) was used for blood flow velocity measurements in the fetal MCA, DA, SA, RA, FA and UA. In the colour Doppler mode, the flow directed toward the transducer was displayed in shades of red and the flow directed away from the transducer was in shades of blue. In the colour and pulsed Doppler mode, the lowest possible measurable velocity was 1.54 cm/s. Pulse repetition frequencies were 1–25 kHz, the maximum penetration depth was 24.6 cm, and the gate width was 1–10 mm. Wall filters (50 Hz) eliminated low-frequency signals occurring from vessel wall motion. The spatial peak temporal average intensity at the maximum amplitude and minimum gate width in simultaneous colour and pulsed Doppler mode was <80 mW/cm2, according to the manufacturer's specification.

The technique of recordings previously described (Manabe et al.,1995Go) has been reported in detail elsewhere. Briefly, a good real-time image of the plane in which the vessel is situated was first obtained and the colour flow function was then superimposed in an attempt to visualize blood flow through the vessel and to minimize the angle of insonation between Doppler beam and flow direction. The pulsed Doppler sample volume (3 mm) was therefore placed on the point of maximum signal intensity as expressed by the degree of colour brightness and the flow velocity waveforms were then recorded. MCA was insonated at the level of the greater wings of the sphenoid. Velocity waveforms from DA were recorded at the lower thoracic level whereas RA waveforms were measured at the level of branching from the abdominal aorta. SA velocity waveforms were obtained at the level of the splenic hirus, and FA velocity waveforms were gained at the level of the upper third of the thigh. UA velocity waveforms were analysed in a position considered equidistant from abdominal and placental insertion points. Unfortunately, DA, RA, SA, and FA velocity waveform measurements in triplet pregnancy could not be performed, because the vessels could not be identified due to fetal crowding.

Recordings were made in the absence of fetal body or breathing movements. Waveforms were recorded over five cardiac cycles. PI [(peak systolic velocity – end-diastolic velocity)/time-averaged mean peak velocity] was calculated. All examinations were performed by one examiner (M.A.). The intra-observer coefficient of variation for the measurement of PI was determined by performing five consecutive examinations on 10 patients within 30 min. The results were 7.5, 8.8, 9.7, 8.5, 7.2 and 9.6% for measurements of PI for MCA, DA, RA, SA, UA and FA respectively.

For each artery in each fetal group, data set regression analysis was carried out, testing the regression of PI value on menstrual age, using polynomials of the first to the third degree (Dunn and Clerk, 1974; Rohatgi, 1976Go; Bertagnoli et al., 1983Go). Different models were tested and independent variable deletion carried out by ANOVA applied to the regression was followed by calculation of the step-down method coefficients (Snedecor and Cochran, 1967). The choice of the optimal model was based on the following criteria: largest R2, all coefficients different from 0, and low standard deviation of regression (SDR) (Bertagnoli et al., 1983Go).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There were no significant differences for the height, weight and parity of the maternal population among the three groups. Birth characteristics of subjects were shown in Table IGo. Birth weight of 35 S-AGA were in the normal range (between the 10th and 90th percentile) to the standard growth curve for the Japanese (Sato et al., 1982Go). Birth weights in Tw-AGA and Tri-AGA infants were compared with the twin weight growth curve for the Japanese (Fukuda, 1989Go), and all fetal weights were appropriate for gestational age.


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Table I. Birth characteristics of subjects
 
The results of the mathematical modelling of the data in S-AGA, Tw-AGA, Tri-AGA fetuses are shown in Table IIGo. The predicted values of each PI for each artery derived from these functions and their variability at different menstrual ages in AGA fetuses are presented in Tables III–VIII. Comparisons of predicted PI values for each artery among the groups are presented graphically in Figures 1–6GoGoGoGoGoGo.


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Table II. Models fitted to the data
 


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Figure 1. Change in pulsatility index values for fetal middle cerebral artery among singleton, twin and triplet pregnancies.

 


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Figure 2. Change in pulsatility index values for umbilical artery among singleton, twin and triplet pregnancies.

 


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Figure 3. Change in pulsatility index values for fetal descending aorta in singleton and twin pregnancies.

 


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Figure 4. Change in pulsatility index values for fetal splenic artery in singleton and twin pregnancies.

 


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Figure 5. Change in pulsatility index values for fetal renal artery in singleton and twin pregnancies.

 


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Figure 6. Change in pulsatility index values for fetal femoral artery in singleton and twin pregnancies.

 
In MCA, models showed the parabolic pattern during pregnancy in S-AGA and Tw-AGA fetuses, whereas those in Tri-AGA fetuses showed a linear pattern (Figure 1Go). However, there was no significant difference in predicted MCA PI value in S-AGA, Tw-AGA and Tri-AGA fetuses. In UA, PI values decreased significantly with increasing menstrual age among the groups (Figure 2Go). PI values in DA remained fairly constant throughout menstrual age, and there was no significant difference in the predicted PI value between S-AGA and Tw-AGA fetuses (Figure 3Go). In SA, the model showed a parabolic pattern during pregnancy in both S-AGA and Tw-AGA fetuses (Figure 4Go). In RA, PI values decreased gradually as menstrual age advanced in both S-AGA and Tw-AGA fetuses (Figure 5Go). In FA, PI values increased significantly with advancing menstrual age in both S-AGA and Tw-AGA fetuses (Figure 6Go).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In a previous investigation (Kuno et al., 1999Go), appropriate-for-gestational-age fetuses were selected as a subject in multiple pregnancies, to avoid the bias contained by other reports on fetal growth in multiple pregnancies (Elster et al., 1991Go; Jones et al., 1991Go; Yuval et al., 1995Go) which included many small-for-gestational-age infants studied in their live-born babies, and tried to evaluate whether growth difference exists among S-AGA, Tw-AGA and Tri-AGA infants in utero. Consequently, there was no significant difference in predicted estimated weight value between Tw-AGA and Tri-AGA fetuses. However, these values were slightly lower than those of S-AGA fetuses. It was suggested that the deposition of soft tissue seen in normal singletons during the third trimester occurs to a much lesser extent in normal twins and triplets (Hata et al., 1991Go; Xu et al., 1995Go). Whether this decrease in soft tissue deposition in multiple pregnancies represents a true growth abnormality or merely a physiological adaptation to the energy demands associated with the support of growth in multiple fetuses is currently unknown. In this study, alterations in fetal vascular resistance of fetal peripheral arteries with advancing gestation in S-AGA, Tw-AGA and Tri-AGA infants were evaluated. In fact, the alterations in various fetal regional arterial pulsatility indices with advancing gestational age showed no significant differences in S-AGA, Tw-AGA and Tri-AGA infants, respectively. Consequently, there is no significant difference for regional arterial vascular resistance in AGA fetuses among singleton, twin and triplet pregnancies, whereas there was a slight difference in fetal growth pattern among singleton, twin and triplet pregnancies described in a previous investigation (Kuno et al., 1999Go). These results suggest that the decrease in soft tissue deposition in multiple pregnancies represents merely a physiological adaptation to the energy demands associated with the support of growth in multiple fetuses.

There have been a few reports on fetal Doppler velocimetry in multiple pregnancies (Nimrod et al., 1987Go; Giles et al., 1990Go; Gaziano et al., 1991Go; Degani et al., 1992Go). However, these Doppler studies were carried out only in MCA and UA. Available data for other fetal peripheral arteries in multiple pregnancies are limited. There is no known report on fetal peripheral arterial Doppler velocimetry, such as SA, RA and FA in multiple pregnancies. Therefore, it was thought that a different standard of fetal Doppler velocimetry in multiple pregnancies was needed for different peripheral arteries. The Doppler ultrasonography-based reference limits constructed in this longitudinal population provide an additional tool for the evaluation of fetal regional vascular resistance in multiple pregnancies. In singleton small-for-gestational-age fetuses, a decrease in the SA-PI (Abuhamad et al., 1995Go; Capponi et al., 1997Go), increase in the RA-PI (Mari et al., 1995Go), and increased FA-PI (Mari et al., 1991) have been reported. Since in this study all fetuses were AGA, one would not expect dramatic differences in comparing these fetuses. However, the results of this study on different fetal peripheral artery PI in multiple pregnancies may have clinical usefulness, especially in the case of discordant fetal growth. Further study is needed to clarify the clinical significance of these measurements in multiple pregnancies.


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Table III. Normal range for pulsatility index (PI) values for middle cerebral artery (MCA)
 

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Table IV. Normal range for pulsatility index (PI) values for umbilical artery (UA)
 

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Table V. Normal range for pulsatility index (PI) values for descending aorta (DA)
 

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Table VI. Normal range for pulsatility index (PI) values for splenic artery (SA)
 

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Table VII. Normal range for pulsatility index (PI) values for renal artery (RA)
 

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Table VIII. Normal range for pulsatility index (PI) values for femoral artery (FA)
 

    Notes
 
1 To whom correspondence should be addressed Back


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 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on April 7, 1999; accepted on June 25, 1999.