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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Okayama University Medical School, Okayama, Japan.
Address reprint requests to: Mikiya Nakatsuka, MD, Okayama University Medical School, Department of Obstetrics and Gynecology, 2-5-1 Shikata, Okayama-City, Okayama, 700-8558 Japan; E-mail: mikiya{at}cc.okayama-u.ac.jp.
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ABSTRACT |
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METHODS: Uterine, ophthalmic, and brachial arterial blood flow of 99 pregnant women (control group [n = 32], non-preeclamptic intrauterine growth restriction group (n = 15), mild preeclampsia group [n = 25], and severe preeclampsia group [n = 27]) were evaluated by pulsed Doppler ultrasound or flow-mediated vasodilation.
RESULTS: Uterine, orbital, and brachial circulation were altered in preeclampsia, whereas no significant differences were observed between the non-preeclamptic intrauterine growth restriction and control groups. Pulsatility index in the uterine arteries of preeclamptic women with intrauterine growth restriction was approximately three-fold higher than that of normotensive women with or without intrauterine growth restriction. The peak ratio (defined to quantify characteristic flow velocity waveform) of the ophthalmic artery of hypertensive women was significantly higher than that of normotensive women. Flow-mediated vasodilation in the brachial artery of preeclamptic women with intrauterine growth restriction was significantly lower than that in preeclamptic women without intrauterine growth restriction. Among preeclamptic women, elevation of the resistance in the uterine artery and reduced flow-mediated vasodilation were closely correlated to intrauterine growth restriction, whereas the elevated peak ratio of the ophthalmic artery was dependent on hypertension, irrespective of the presence of intrauterine growth restriction.
CONCLUSION: Ultrasound evaluation of uterine and orbital circulation and flow-mediated vasodilation of the brachial artery helps differentiate the degree and severity of preeclampsia.
Normal pregnancy is associated with vasodilation and decreased peripheral resistance, which is detected as early as 5 weeks’ gestation.1 Preeclampsia has been recognized as a syndrome characterized by profound dysfunction of the vascular endothelium.2,3 Increased resistance to blood flow in the uterine arteries precedes the onset of preeclampsia4,5 and leads to impaired fetoplacental circulation and consequent fetal growth restriction.
The visual system is also frequently affected in hypertensive disorders, including preeclampsia.6 The orbital circulation during pregnancy with or without preeclampsia has been evaluated by pulsed Doppler ultrasonography measuring various indexes of the ophthalmic artery, central retinal artery, and posterior ciliary artery.7–12
In contrast with these static blood-flow evaluations of the uterine arteries or the ophthalmic arteries, evaluating dynamic vascular changes under shear stress conditions may elucidate latent endothelial dysfunction in preeclampsia. Shear stress is the frictional force at the endothelial surface that results from intraluminal flow and is considered to be an important physiological stimulus to nitric oxide–mediated vasodilation.13 This response is detected in the human radial artery by ultrasonography and is enhanced during pregnancy.14 An important functional consequence of endothelial dysfunction is the inability to release nitric oxide.15 Cockell and Poston13 and Sladek et al16 reported that flow-mediated vasodilation and nitric oxide synthesis are impaired in women with preeclampsia. Measurement of flow-mediated vasodilation is a noninvasive technique that is useful in assessing endothelial dysfunction, including compromised nitric oxide production.
There are wide spectra of degrees in preeclampsia with respect to blood pressure and fetal growth. Individual reports4–14,16 on pulsed Doppler findings of umbilical artery, fetal middle cerebral artery, uterine artery, maternal ophthalmic artery, or flow-mediated vasodilation demonstrated a significant alteration of blood flow in preeclamptic women. There is, however, variation among preeclamptic women. We surmised that a combination of these techniques may provide a clearer differentiation and may help elucidate the pathophysiology of preeclampsia.
In the present study, we assessed local constrictions in uteroplacental and maternal orbital and brachial circulation in women with preeclampsia, as representatives of systemic vascular beds. We also evaluated the reserved ability of the brachial artery to release nitric oxide from vascular endothelium by measuring flow-mediated vasodilation. We thus developed a method that differentiates the degree and severity of preeclampsia based on noninvasive ultrasonography to improve the ability to deal with characteristic endothelial dysfunction, which often leads to hypertension, impaired fetoplacental circulation, and consequent fetal growth restriction.
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MATERIALS AND METHODS |
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Preeclampsia was defined as blood pressure greater than 140/90 mm Hg and 1 + or greater proteinuria. Severe preeclampsia was defined as systolic blood pressure greater than 160 mm Hg, diastolic blood pressure greater than 110 mm Hg, or proteinuria greater than 5 g per 24 hours. Patients with chronic hypertension, which was defined as the presence of systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg predating the pregnancy or before 20 weeks’ gestation, were excluded from the study. Growth-restricted fetus (intrauterine growth restriction) was diagnosed when Doppler studies were performed and was confirmed by birth weight of less than the tenth centile for gestation. We used a nomogram reported from the Ministry of Health & Welfare of Japan (1998). Nonpreeclamptic women with an intra-uterine growth-restricted fetus were included among the subjects; causes of growth restriction were marginal insertion of the umbilical cord, placental infarction, fetal minor heart anomaly, and fetal viral infection. Small-for-gestational-age fetuses without any abnormality were excluded after examinations of the neonate, the placenta, and the umbilical cord.
Normotensive pregnant women without complications were defined as controls. Control women from our outpatient clinic, who voluntarily participated in our study, visited our hospital for ultrasonographic evaluation. We performed ultrasonographic evaluation of women with intrauterine growth restriction or preeclampsia when they were admitted to our hospital. Women who were presenting to labor and delivery were excluded as subjects. Ultrasonographic evaluation was performed at 32.2 ± 3.9 (mean ± standard deviation [SD]) weeks’ gestation in the control group, 32.4 ± 4.7 in the intrauterine growth restriction group, 32.6 ± 4.1 in patients with mild preeclampsia, and 32.3 ± 2.7 in patients with severe preeclampsia. Ultrasonographic data in the present study were obtained before starting medication. Clinical features and obstetric outcome of these women are shown in Table 1
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Ultrasonographic evaluation of the ophthalmic artery of pregnant women was performed using a 5-MHz probe (Aloka SSD-2200 scanner). The subjects were examined in a supine position after at least 5 minutes of bed rest. Ophthalmic arteries were observed as described previously.12,20–22 Pulsatility index, resistance index, peak systolic velocity, end-diastolic velocity, and time-averaged mean peak velocity in the ophthalmic artery were measured by color-image pulsed Doppler ultrasonography. We defined the peak ratio as the ratio of the flow velocity of the second peak to that of the initial peak (Figure 1) to quantify characteristic changes in the ophthalmic artery flow velocity waveform in preeclampsia.12 The average value of the bilateral ophthalmic arteries was calculated.
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Vessel diameters were measured with ultrasonic calipers, from the anterior to the posterior interface between media and adventitia, as previously reported.21 Flow-mediated vasodilation was calculated as the percentage change in diameter following reactive hyperemia (the maximal dilation) to the baseline (at rest) scans. Recovery time was defined as the interval between the time when the maximal vasodilation was detected and the time at the end of reactive hyperemia. Measurement of flow-mediated vasodilation was performed by one person. Intraobserver variability of the brachial artery diameters recorded five times on the same occasion was 0 ± 0.09 mm, with a coefficient of variability of 3.1%.
For data on umbilical artery/middle cerebral artery PI ratio, week of delivery, birth weight, and Apgar score in Table 1
and data in Figures 2, 3, and 4, significant difference were determined by Kruskal-Wallis test, and each group was compared to the control group by Mann-Whitney U test. After Bonferroni correction, a P value of less than .017 (Table 1) or a P value of less than .003 (Figures 2, 3, and 4) was considered statistically significant. Data are presented as median [range] in Table 1. For the other data in Tables 1, 2, and 3, statistical significance were determined by one-way analysis of variance and Dunnett post-hoc procedure, or 
2 test for independence. Data are presented as mean ± SD, and statistical significance was defined as P < .05.
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RESULTS |
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). In each group with preeclampsia, the rate of cesarean delivery was higher than that in the control group. The Apgar score at 1 minute was significantly lower in preeclamptic women than in control women. The PI in the uterine artery (percent of standard value for gestation) was 106.6% ± 37.3% (mean ± SD) in control women, 128.9% ± 39.9% in women with intrauterine growth restriction, 229.2% ± 65.6% in women with mild preeclampsia, and 302.2% ± 98.2% in women with severe preeclampsia. The PI in the uterine artery of preeclamptic women was significantly higher than that of control women, whereas there was no significant difference in uterine artery PI between women in the intrauterine growth restriction group and control women (P < .001). The PI in the uterine artery of women with severe preeclampsia was significantly higher than that of women with mild preeclampsia (P < .005).
Various indexes in the ophthalmic artery in preeclamptic women were significantly different from those in control women (Table 2); however, there were no significant differences in indexes in the ophthalmic artery between women in the intrauterine growth restriction group and control women. The peak ratio in the ophthalmic artery in women with severe preeclampsia was significantly higher than that in women with mild preeclampsia (P < .001), whereas the other indexes were not significantly different.
Pulsatility index in the brachial artery was reduced by flow-mediated vasodilation (Table 3). Reduction of PI in the brachial artery of women with severe preeclampsia was greater than that of control women; however, there was no significant difference in reduction of PI between women with mild preeclampsia and control women or between women in the intrauterine growth restriction group and control women.
Flow-mediated vasodilation in women with mild preeclampsia was significantly lower than that in the control group. The flow-mediated vasodilation recovery time in women with mild preeclampsia was also significantly lower than that in control women.
Severe hypertenstion was defined as systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 110 mm Hg. Mild hypertension was defined as systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg. Based on the above definitions, we divided the preeclamptic women into four groups: mild hypertension group (n = 15): mild hypertension and an appropriate-for-gestational-age (AGA) fetus; mild hypertension–intrauterine growth restriction group (n = 10): mild hypertension and an intrauterine growth-restricted fetus; severe hypertension group (n = 11): severe hypertension and an AGA fetus; and severe hypertension–intrauterine growth restriction group (n = 16): severe hypertension and an intrauterine growth-restricted fetus.
Women with intrauterine growth restriction (intrauterine growth restriction group, mild hypertension intrauterine growth restriction group, or severe hypertension intrauterine growth restriction group) had a significantly higher rate of cesarean delivery, whereas there was no significant difference in the rate of cesarean delivery between preeclamptic women without intrauterine growth restriction and control women. The Apgar score at 1 minute was also significantly lower in the mild hypertension–intrauterine growth restriction group and severe hypertension–intrauterine growth restriction group than that in the control group, whereas no significant difference was observed between preeclamptic women without intrauterine growth restriction and control women. The Apgar score in the severe hypertension–intrauterine growth restriction group was significantly lower than that of women in the severe hypertension group (P < .001). This score in the mild hypertension–intrauterine growth restriction group was also significantly lower than that of women in the mild hypertension group (P < .005).
The umbilical artery/middle cerebral artery PI ratio of women in the mild hypertension group, the mild hypertension–intrauterine growth restriction group, the severe hypertension group, and the severe hypertension–intrauterine growth restriction group was 0.592 ± 0.159 (mean ± SD), 1.016 ± 0.400, 0.592 ± 0.187, or 1.241 ± 0.852, respectively. This ratio in the intrauterine growth restriction group, in the mild hypertension–intrauterine growth restriction group, or in the severe hypertension–intrauterine growth restriction group was significantly higher than that in the control group (P < .03, P < .005, P < .001, respectively). The umbilical artery/middle cerebral artery PI ratio of women in the severe hypertension–intrauterine growth restriction group was significantly higher than that of women in the severe hypertension group (P < .001). This ratio in the mild hypertension–intrauterine growth restriction group was also significantly higher than that in the mild hypertension group (P < .02).
The PI in the uterine artery of preeclamptic women was significantly higher than that of women in the control group (Figure 2). The PI in the uterine artery of preeclamptic women with an intrauterine growth-restricted fetus was significantly higher than that of preeclamptic women without an intrauterine growth-restricted fetus.
On the other hand, elevation of the peak ratio in the ophthalmic artery correlated with the elevation of blood pressure (Figure 3). The peak ratio in preeclamptic women was significantly higher than that in normotensive women (control group or intrauterine growth restriction group). There was no significant difference in peak ratio between women in the mild hypertension group and women in the mild hypertension–intrauterine growth restriction group or between women in the severe hypertension group and women in the severe hypertension–intrauterine growth restriction group.
Flow-mediated vasodilation of women in the mild hypertension–intrauterine growth restriction group or the severe hypertension–intrauterine growth restriction group was significantly lower than that in the control group (Figure 4). Flow-mediated vasodilation in preeclamptic women with an intrauterine growth-restricted fetus was significantly lower than that of preeclamptic women without an intrauterine growth-restricted fetus.
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DISCUSSION |
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In the present study, elevated uterine arterial PI was observed in patients with severe hypertension without intrauterine growth restriction as a manifestation of systemic vasoconstriction; however, it was prominent in patients with mild or severe hypertension with intrauterine growth restriction. These results are consistent with previous reports that abnormality of the uterine artery PI provides a good predictor of poor perinatal outcome6,7; however, this is likely to be valid only in preeclampsia. Because elevation of uterine arterial resistance was not observed in non-preeclamptic women with intrauterine growth restriction, this group should be treated differently, and other causes of fetal growth restriction should be investigated, for instance, factors of fetal origin, umbilical cord, or placenta.
Pulsed Doppler examination of the maternal ophthalmic artery is a useful adjunct to the management of pregnancy-induced hypertension.9,10 Hata et al10 reported that preeclampsia was associated with a significant decrease in ophthalmic artery vascular resistance, which is interpreted as orbital hyperperfusion or hyperemia. Our data are consistent with their reports. In contrast with uterine arteries, alteration of resistance in the ophthalmic artery was dependent on hypertension, irrespective of the existence of intrauterine growth restriction. We have found that the peak ratio was a sensitive index in detecting changes in the orbital circulation of preeclamptic women, and this index is more sensitive in detecting the effects of a nitric oxide donor than other indexes.12
Hata and Miyazaki22 reported that resistance in the ophthalmic artery is reduced in normotensive pregnant women with a growth-restricted fetus as compared with those with an AGA fetus. As shown in Figure 3, however, we observed no significant difference between the control group and the intrauterine growth restriction group, mild hypertension group and mild hypertension intrauterine growth restriction group, or severe hypertension group and severe hypertension–intrauterine growth restriction group. The reason for this discrepancy is uncertain. Unfortunately, Hata and Miyazaki22 did not provide data on the resistance of uterine arterial blood flow or flow-mediated vasodilation. The subjects of their study may have included normotensive women with subclinical vascular abnormality. We strictly excluded from the intrauterine growth restriction group women who exhibited a preeclamptic tendency later and those with a smoking habit. The differences among the subjects recruited in their study and ours may explain this discrepancy. Because the sample size is relatively small in some groups of our study, further large-scale study may also be necessary.
Flow-mediated vasodilation is endothelium dependent,13–15,21,23,24 and attenuated dilatory responses are observed in subjects with early vascular damage in atherosclerosis or diabetes mellitus.15,21 Because some of the women could not endure a longer cuff occlusion because of pain, we adopted a 2-minute cuff occlusion to measure the flow-mediated vasodilation, which is approximately half the maximal increase of forearm blood flow observed after a 10-minute cuff occlusion.23 To ensure compliance of this test, we measured flow-mediated vasodilation after cuff occlusion for 2 minutes, although sensitivity may be slightly lower than with a longer occlusion.
In the present study, flow-mediated vasodilation in the brachial artery was closely correlated with intrauterine growth restriction when intrauterine growth restriction was associated with preeclampsia. This observation is similar to the results in the PI of the uterine artery. In patients with reduced flow-mediated vasodilation in the brachial artery, impairment of flow-mediated vasodilation in the uterine artery is likely to be observed concomitantly. These patients may have impaired uterine circulation because the uterine artery is susceptible to shear stress caused by contraction and relaxation of uterine muscle.
Cockell and Poston13 hypothesized that enhanced responses to shear stress, which leads to enhanced nitric oxide release, may play an important role in the adaptation of the maternal circulation to pregnancy. Studies using an inhibitor of nitric oxide synthase16 or a nitric oxide donor25,26 also support that compromised nitric oxide production is likely to be a common feature of preeclamptic women with intrauterine growth restriction and that consequent vasoconstriction causes a decline in uteroplacental circulation as compared with the elevation of blood pressure.
In the present study, pulsed Doppler findings of maternal uterine artery, maternal ophthalmic artery, or flow-mediated vasodilation vary among preeclamptic women. Therefore, a combination of these techniques is required to differentiate the type and severity of preeclamptic women as well as non-preeclamptic women with a growth-restricted fetus. Our method of combined ultrasound evaluation of maternal uterine artery, maternal ophthalmic artery, and flow-mediated vasodilation is useful in understanding the status of systemic circulation in the individual preeclamptic women and helps differentiate the degree and severity of preeclampsia. Further study may help in providing more appropriate treatment for preeclamptic women. Elevation of resistance in uterine arterial flow is detected before the onset of preeclampsia,4,5 and impaired flow-mediated vasodilation is detected in young subjects with risk factors before the onset of cardiovascular disease.15 Therefore, our method of ultrasound evaluation may also predict the onset of preeclampsia or fetal growth restriction more precisely than by individual measurement.
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Footnotes |
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Received January 30, 2002. Received in revised form May 17, 2002. Accepted June 27, 2002.
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REFERENCES |
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