PEDIATRICS Vol. 118 No. 3 September 2006, pp. 1035-1041 (doi:10.1542/10.1542/peds.2006-0386)
ARTICLE |
Stiffness of Systemic Arteries in Appropriate- and Small-for-Gestational-Age Newborn Infants
Department of Obstetric and Gynecology, Tokai University School of Medicine Isehara-City, Kanagawa, Japan
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. The purpose of this work was to study the stiffness of systemic arteries in appropriate and small for gestational age newborn infants. The distance between diametrically opposite points of the arterial lumen was measured with a phase locked loop echo tracking system coupled to a B-mode ultrasonic imager.
PATIENTS AND METHODS. A cross-sectional study of 51 appropriate for gestation age infants including 22 preterm infants was done to obtain normal data. We also studied 47 small for gestational age infants, who were identified antenatally by an umbilical artery Doppler flow waveform pulsatility index >95th percentile. The stiffness index of the common carotid artery and abdominal aorta was calculated from the relationship between systemic blood pressure and arterial diameter during the cardiac cycle.
RESULTS. In the appropriate for gestation age group, the systolic and diastolic diameters of the common carotid artery and abdominal aorta, as well as the stiffness index, increased with the gestational age at birth. In the small for gestational age group, the arterial diameters and blood pressure were also within the reference range. Using the arterial stiffness index values from the appropriate for gestation age group, the small for gestational age group was divided into 3 subgroups: 18 infants with normal stiffness index values for both arteries, 19 infants with a high stiffness index of the abdominal aorta, and 10 infants with a high stiffness index for both arteries. The clinical outcome was significantly worse in the latter 2 subgroups compared with the normal infants and was also worse in the infants with a high stiffness index for both arteries compared with the high abdominal aorta subgroup.
CONCLUSION. The antenatal increase of afterload caused by a high placental vascular resistance was associated with a decrease of aortic distensibility in the compromised small for gestational age infants, suggesting that the structure of the aortic wall was altered. In the most profoundly compromised small for gestational age infants, the high stiffness index of both the common carotid artery and abdominal aorta may indicate more extensive arterial damage.
Key Words: umbilical placental insufficiency • newborn infant • stiffness • intrauterine growth restriction
Abbreviations: IUGR—intrauterine growth restriction • SGA—small for gestational age • CCA—common carotid artery • AA—abdominal aorta • AGA—appropriate for gestational age • SI—stiffness index • bpm—beats per minute • FHR—fetal heart rate
The term "placental insufficiency" has long existed in obstetrics to indicate a state of inadequate blood flow through the placenta. It is associated with the fetal syndrome of intrauterine growth restriction (IUGR) that results in the birth of small for gestational age (SGA) neonates. IUGR is associated with profound fetal circulatory changes. Examination of vascular pathology in the umbilical placental circulation has revealed the occurrence of thrombosis; vessel obliteration; and platelet activation/consumption.1 These changes have been reported to increase the afterload on the heart in SGA fetuses.2
There is current interest in the possibility that an adverse in utero environment may alter the structure, physiology, and metabolism of the fetus and, thus, may influence the risk of cardiovascular disease in later life.3 It has been demonstrated that early aortic atherosclerosis can be detected in human fetuses.4 Reduced blood flow to the peripheral circulation may alter the structure and compliance of the fetal arteries, resulting in the development of systemic hypertension later in life.
Quantitative information about the elastic properties of the large arteries can be obtained by determination of the pressure and the pulsatile changes of arterial diameter.5 We developed a paired ultrasonic phase locked echo tracking system with a high sampling frequency coupled to a B-mode ultrasonic imager.6 The neonatal heart rate is twice that of adults, so a high sampling frequency is important to enable wall motion to be accurately tracked throughout the whole cardiac cycle in order for the changes of vessel diameter to be faithfully recorded. In the present study, we used this ultrasonic technique to compare the distensibility of the common carotid artery (CCA) and abdominal aorta (AA) in appropriate for gestational age (AGA) infants versus SGA infants born after suffering from placental insufficiency. Quantitative assessment of the arterial changes caused by placental insufficiency may help to improve prediction of the clinical outcome.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We studied 2 groups of newborn infants who were AGA and SGA. The AGA group consisted of the fetuses of 315 pregnant women in whom there was ultrasound confirmation of gestational age. Patients who smoked and those having known pregnancy complications, such as multiple pregnancy and maternal illness, were not enrolled in the AGA group. Twenty-seven of the 315 fetuses were delivered before 37 weeks because of cervical incompetence or ruptured membranes. The antenatal umbilical artery Doppler flow waveform pulsatility index was within reference range. Fifty-nine AGA infants with normal pulsatility index, including 27 preterm infants who were studied longitudinally at weekly intervals until delivery (>3 times), served as the control subjects.
An additional 140 pregnant women had fetal growth monitoring in the fetal welfare laboratory, because the pregnancy was considered to be at risk. The study was performed between 29 and 40 weeks. The principal associated obstetric complication was maternal hypertension (n = 44), suspected growth failure (41), premature labor (n = 24), antepartum hemorrhage (n = 20), maternal diabetes mellitus (n = 7), and maternal renal disease (n = 4). In this group, 56 SGA infants who were studied longitudinally at weekly intervals until delivery were selected (>3 times). The SGA infants were defined as follows: (1) no malformation or chromosomal defect; (2) ultrasound measurement of fetal abdominal circumference with flattening growth pattern (<10th percentile) below the mean of our reference range; (3) pulsatility index (>95th percentile) above the mean of our reference range of the antenatal umbilical artery Doppler flow waveform, indicating increased downstream resistance and umbilical placental insufficiency; and (4) postnatal confirmation of a birth wight (<10th percentile). They were studied during first 2 hours after birth. In all of the cases, informed consent was obtained from their parents to participate in this study.
The infant arterial diameter pulse waveforms were recorded from right CCA (1–2 cm prominal to its bifurcation) and AA (1–2 cm distal to the branching site to the superior mesenteric artery) during first 2 hours after birth. The distance between diametrically opposite points of the vessel lumen was followed using a paired phase locked loop echo tracking system coupled to a B-mode ultrasonic imager (Aloka 650 special version [Aloka, Tokyo, Japan]). The central frequency of the ultrasonic probe was 5 MHz. The details of the system have been reported elsewhere.6 The ultrasonography signal was converted into an analog output. For analysis of the diameter pulse waveforms the analog voltage representing the vessel diameter was processed using the computer with a MacPac (Goleta, CA) peripheral.
The following characteristics of the diameter pulse wave form were measured: (1) peak systolic diameter (millimeters); (2) end-diastolic diameter (millimeters); (3) mean diameter (millimeters), which was calculated from the mean over the cardiac cycle; (4) pulse amplitude, of which the difference between the systolic and diastolic diameters were expressed in absolute terms (millimeters); (5) pulse amplitude ratio (percent stroke change in diameter), the ratio of the pulse amplitude to the diastolic diameter, which was expressed as a percentage; and (6) the ventricular ejection time, which was calculated using the first derivative waveform to locate the incisura and, thus, the time of closure of the aortic and pulmonary valves (Fig 1).
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Newborn Infants' Blood Pressure
A Dinamap oscillometric monitor (Critikon Inc, Tampa, FL), which has been demonstrated to be reliable, was used to measure blood pressure during the first 2 hours of life in the newborn infants.7 The measurements were made on both upper arms and the right lower limb (calf) in duplicate, with the infant lying supine. The mean of the 2 readings obtained at each site was used for analysis; if any movement occurred during the recording, the whole procedure was repeated. We did not include the values for their blood pressures during resuscitation. All of the infants had to fulfill the following criteria: Apgar score >5 at 1 minute and >7 at 5 minutes and no evidence of respiratory distress, sepsis, central depression, or cerebral irritation.
The distensibility or stiffness of the arterial wall was analyzed using the pressure-diameter relation by Hayashi and colleagues.8 The stiffness index (SI) was calculated as:
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The ultrasonic and blood pressure measurements were performed for each study interval during periods of rest without movement. The measurements were made without knowledge of antenatal assessment during the first 2 hours of life in clinically stable, untransfused infants. Data from 10 consecutive diameter pulse waveforms were calculated and averaged for each measurement.
For the arterial distensibility measurements, data (intraobserver and interobserver) reproducibility was assessed. Intraobserver reproducibility of the CCA and AA was assessed in 5 AGA infants at 32, 34, 36, 38, and 40 weeks at birth, 3 times for each infant. The same examiner measured the SI at intervals of 5 to 10 minutes to obtain the mean value, SD, and coefficient of variation (SD/mean). Moreover, 3 observers (interobserver reproducibility) measured the SI in 2 AGA infants at 34 and 38 weeks at birth. The intraobserver and interobserver coefficient of variation was 5.9% (CCA) and 6.1% (AA) and 7.1% (CCA) and 7.8% (AA), respectively. The antenatal umbilical artery flow velocity waveform was recorded using a method reported previously.1,6
Statistical Analysis
The 5th and 95th percentiles of the normal studies were determined using the method of Royston9 and Altman,10 which permits a parametric derivation of an age-related variable and allows for a nonlinear relationship between variability and age. These studies were performed with the approval of the Hospital Research and Ethics Committee.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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AGA Infant Group
Initially, 59 infants were enrolled in the study. Complications of birth, including asphyxia (Apgar score <5 at 1 minute; 4 infants), septicemia (3 infants), and suspected central nervous system hemorrhage (1 infant), reduced the number to 51 newborn infants who weighed 1652 to 3280 g (2618 ± 483, mean ± SD) at birth. The gestational age at delivery ranged from 32 to 40 weeks (36.5 ± 2.5, mean ± SD; Table 1).
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In the AGA infant group, the pulse duration showed an increase, corresponding with a decreasing mean infant heart rate from a mean (SD) of 140.2 (6.6) beats per minute (bpm) at 32 to 34 weeks of gestational age at birth to 125.8 (6.4) bpm at 38 to 40 weeks of gestational age at birth. There was no significant change in the mean ventricular ejection time from 0.185 seconds at 32 to 34 weeks to 0.187 seconds at 37 to 40 weeks. The changing heart rate over this period was associated with a changing diastolic time period. In both CCA and AA, there was an increase of the systolic and diastolic diameters, as well as blood pressure, with advancing gestational age at birth (Table 2).
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The pulse amplitude of both the arteries increased but showed a small decrease when expressed as a percentage of the diastolic diameter (Table 2). The SI for each newborn infant was plotted against the infant's gestational age at birth for each portion of the arterial tree. It was found that the SI of the arteries increased linearly with advancing gestational age at birth (Fig 2, CCA, top, and AA, bottom).
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, actual regression line (CCA: y = 0.159x –1.528; r = 0.703; P < .001; AA: y = 0.169x –1.9; r = 0.834; P < .001); —, 95% confidence limits for the AGA infant group.SGA Infant Group
The SGA group included 56 infants born after umbilical placental insufficiency as fetuses. Nine infants (16.1%) were excluded from this study because of any of the following: they survived <48 hours (2 infants); they had birth asphyxia (Apgar score <5 at 1 minute; 3 infants); they had septicemia (2 infants); or they were suspected of having central nervous system hemorrhage (2 infants). The results from the 47 SGA infants (birth weight <10th percentile) who weighed 1147 to 2320 g (1757 ± 396, mean ± SD) at birth were compared with the data from the AGA infant group (Table 1). The gestational age at delivery ranged from 32 to 40 weeks (35.7 ± 2.9, mean ± SD). Differences for each parameter between the AGA and SGA infant groups were examined using analysis of variance with gestational age at birth as the covariate.
There were no significant differences of the mean heart rate and ventricular ejection time between the AGA and SGA infant groups. The heart rate was not correlated with the individual dimensions or the blood pressure. In both CCA and AA, the differences of peak systolic and end-diastolic dimensions were not significant. The pulse amplitude ratio of the CCA tended to be lower, but this difference did not reach statistical significance (Table 1). That of the AA was reduced. The diastolic dimension of the AA was expressed relative to the infant abdominal circumference. This was expressed as a percentage. It was considered that infant abdominal size might influence the aortic size. Normal range for the AGA infant group was defined. There was no significant change in the ratio from 2.08% ± 0.11% (mean ± SD) at 32 to 34 weeks to 2.1% ± 0.17% at 38 to 40 weeks (Fig 3, top). An example of a recording of the aortic diameter pulse waveform from an AGA infant at 33 weeks of gestation at birth is shown in Fig 1 (left panel). The diastolic dimension (5.58 mm) per abdominal circumference (275 mm) was 2.03%. This ratio was high in the SGA group (Table 1). The systolic and diastolic blood pressures were not different. The SI values of the CCA (Fig 4, top) and AA (Fig 4, bottom) were displayed in the figures using data from the AGA infant group to represent 5th and 95th centile limits. The SGA group was divided into 3 subgroups: 18 infants with normal SI values for both arteries (normal subgroup), 19 infants with a high SI of the AA (1-vessel subgroup), and 10 infants with a high SI for both arteries (2-vessel subgroup).
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, normal group (SGA infants with normal aortic and carotid SI values, n = 19); x, 1-vessel subgroup (SGA infants with high aortic SI value, n = 18); 
, 2-vessel subgroup (SGA infants with high aortic and carotid SI values, n = 10).
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To further define the compromised SGA infants, we reviewed the clinical course (Table 3). Pregnancy complications (maternal diabetes, maternal renal disease, pregnancy-induced hypertension, and oligohydramnios) known to be associated with IUGR were similar in all 3 of the groups.
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The result of the antenatal nonstressed fetal heart rate (FHR) recording performed closest to delivery was examined. A nonreactive tracing (variability <5 bpm, no reactions to movement, with or without late decelerations) was present in all infants of the 2-vessel subgroup. Only 5 of the 1-vessel subgroup exhibited a nonreactive FHR tracing. None of the 18 infants from the normal subgroup showed this FHR pattern. The 2-vessel subgroup was delivery earlier (mean gestational age at delivery ± SD, 33.6 ± 1.4 weeks) in comparison with the 1-vessel subgroup (35.6 ± 2 weeks; P < .01, unpaired t test). Birth weight and percentile birth weight were lower in the 2-vessel subgroup. The diastolic dimension per unit abdominal circumference was increased in the 2-vessel subgroup (Fig 3, bottom). An example of a recording of the aortic diameter pulse wave form from an SGA infant (33 weeks at birth) of the 2-vessel subgroup is shown in Fig 1 (right panel). The diastolic dimension (6.08 mm) per abdominal circumference (251 mm) was 2.42%. The infants of the 2-vessel subgroup had a significantly higher rate of neonatal complications, such as metabolic complications (hyperbilirubinemia, hypocalcemia, and hypoglycemia), thrombocytopenia, chronic lung disease, and necrotizing enterocolitis. The requirement for neonatal nursery care (days) was also greater. There were no neonatal deaths in our study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We used a phase locked loop tracking system coupled to a B-mode ultrasonic imager to study the SI of systemic arteries in newborn infants with birth weights of 1147 to 3280 g. There have been no published reports of the elastic properties of the systemic arteries in newborn infants including preterm infants born at an early gestational age. The SI is expressed by the logarithmic slope of relative pressure and by the pulse amplitude ratio.5,8
In both CCA and AA of the AGA infant group, there was an increase of the systolic and diastolic diameters and pulse amplitude with advancing gestational age at birth. The pulse amplitude as a percentage of diastolic diameter tended to decrease. The systolic and diastolic blood pressures also increased. We observed a decrease in arterial distensibility of the CCA and AA with advancing gestational age at birth. Systemic blood pressure has been found to increase during fetal development in a number of species, and this increase is accompanied by characteristic morphologic changes of the arterial wall.11 The increase in the SI of the CCA and AA has been suggested to not only result from changes in structure in the wall, but may also be because of augmented relative wall thickness secondary to increases of vessel caliber and wall thickness.
Although the absolute dimensions of the CCA and AA, as well as the blood pressure, did not differ between the AGA and SGA groups, the diameter per unit of abdominal circumference was larger in the SGA group. The SI of the AA was also higher than expected from the gestational age at birth in compromised SGA infants born after suffering from placental insufficiency. This would seem reasonable, because high placental resistance leads to a major increase of fetal ventricular afterload.12 As a result of the increased stiffness and enlarged caliber of the AA, it retains a larger blood volume at end diastole. This increases the inertial resistance to ventricular ejection and has a considerable effect on myocardial performance. The increased stiffness may contribute to the pathogenesis of hypertension.13 The most severely compromised SGA infants showed a high SI of the CCA in addition to a high SI of the AA, indicating more advanced arterial damage. Clinical outcome (nonreactive FHR, percentile birth weight, and neonatal complications) was significantly worse in the infants with a high SI for both arteries.
In compromised SGA infants, the fetal circulation shows selective modification of peripheral vascular resistance, which leads to preferential perfusion of the brain with respect to the lower body. Cerebral blood flow may increase while flow to the trunk decreases, which represents the so-called brain-sparing effect. At birth, these infants have asymmetrical growth restriction and little subcutaneous fat. We found that the diastolic dimension per unit of abdominal circumference was the highest in the most severely compromised SGA infants. These infants had a higher incidence of metabolic complications (hyperbilirubinemia, hypocalcemia, and hypoglycemia), necrotizing enterocolitis, and chronic lung disease, probably because of end-organ damage in utero from chronic placental insufficiency. Moreover, these infants showed a high SI of the CCA. The preferential perfusion of the fetal head that occurs in severe IUGR may accelerate damage to the CCA. It has been reported that the increase of carotid stiffness during the neonatal period persists in 9-year-old children with a history of low birth weight.14 However, the increase of aortic stiffness is no longer detectable in childhood.15 This may be because of a marked increase in aortic compliance between 4 and 11 years of age.16 In the AGA infants, there was no significant difference of SI between these 2 arteries. The elastic properties of the large arteries are not uniform throughout the vascular tree and also exhibit differential changes over time. For example, the CCA is normally stiffer than the AA in children and young adults.17 During aging, however, stiffness increases more in the AA, and it is stiffer than the CCA from middle age onward.18 It may be possible that a high aortic stiffness because of fetal causes can recur at a later age when aortic stiffness increases as part of the normal aging process.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our method provides a reliable, noninvasive way of measuring the mechanical properties of the large vessels. Serial noninvasive evaluation of aortic stiffness will allow the early detection of physiologic changes during the developmental process. We suggest that the pathophysiological mechanisms that ultimately lead to arterial disease may be initiated in utero.
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FOOTNOTES |
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Accepted Apr 10, 2006.
Address correspondence to Mori Akira, MD, Department of Obstetric and Gynecology, Tokai University School of Medicine Boseidai, Isehara-City, Kanagawa, 259-1193, Japan. E-mail: mor11{at}is.icc.u-tokai.ac.jp
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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