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Elevated Doppler Indices in the Uterine Arteries as a Measure of Impedance to Blood Flow in the Uteroplacental Circulation
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Evidence that elevated S/D ratios, RI, and PI, and the presence of a diastolic notch in the uterine artery flow velocity waveform reflects increased impedance to blood flow in the placental circulation comes from 3 sources: computer models of the uteroplacental circulation,84,85 embolization of the uteroplacental circulation in animal models,86,87 and studies correlating histologic evaluation of placental bed biopsies with Doppler velocimetry of the uterine arteries.88,89
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Computer Models of the Uteroplacental Circulation
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The uterine artery flow velocity waveform has 2 components: a pulsatile component and a steady flow component. The pulsatile component is formed by the interaction of an outgoing wave and a reflected wave, which bounces back to the maternal heart upon reaching the uteroplacental vascular bed.
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Adamson et al84 developed a computer model to evaluate the effect of placental resistance, arterial diameter, and blood pressure on the shape of the uterine artery velocity waveform. Their model was designed to simulate resistance to flow, vessel compliance, and main uterine artery blood inertia, as well as the physical properties of all the vessels branching from the main uterine artery to form the distal vascular bed (arcuate, radial, and spiral arteries). The variables analyzed (uteroplacental vascular resistance, uterine artery radius, and mean arterial blood pressure or MAP) were altered over realistic ranges, either independently or in combination, to examine their effects on the uterine artery flow velocity waveform. When the resistance of the distal vascular bed was increased 6-fold, while keeping the uterine artery radius and MAP constant (Figure 10-17), the following observations were made: (1) decreased mean velocity and blood flow; (2) elevated PI and S/D ratios; and (3) development of a notch in the early diastolic portion of the flow velocity waveform, caused by destructive interaction between outgoing and reflected waves.
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A reduction in the uterine artery radius resulted in an increase in mean velocity, elevated PI and S/D ratios, but no diastolic notch. An increase in the MAP caused elevation in mean blood velocity without changing the RI, or generating a diastolic notch. Importantly, these observations suggest that changes in uterine artery Doppler velocimetry observed in preeclampsia are not mediated by high blood pressure, but rather are the consequence of an abnormally elevated uteroplacental vascular resistance, expressed by elevations in Doppler indices and the presence of a diastolic notch.
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Talbert85 proposed another model to study uteroplacental blood flow. The model used resistance and capacitance elements in all components of the uteroplacental circulation, making it possible to simulate various physiologic situations and observe changes in the Doppler flow velocity waveforms. Uteroplacental blood flow parameters were changed within physiologic limits for a 1000-g human fetus at 28 weeks' gestation. The first experiment described was a 33% reduction in blood flow, achieved by raising the resistance to flow in the transcotyledonary region and spiral arteries. The results were increased uterine artery PI and RI, but no diastolic notch. In the second experiment, intervillous obstruction was modeled by increasing central cotyledon pressure by nearly doubling transcotyledonal resistance, which caused distention and reduction of flow resistance of the spiral and radial arteries. The uterine artery PI and RI increased, but no diastolic notch was produced. When placental resistances were kept within normal limits, and the distensibilities of uterine and arcuate artery walls were raised, a diastolic notch was produced, with normal uterine artery PI and RI. Thus, the typical flow velocity waveforms observed in vivo in abnormal uterine artery Doppler studies (increased PI, RI, and the presence of a diastolic notch) was produced by a combination of increased placental resistance and distensibility of the uterine and arcuate artery walls.
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Embolization of the Uteroplacental Circulation of Pregnant Ewes
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Ochi et al86,87 embolized the uterine spiral arteries of pregnant ewes at 16 to 17 weeks of gestation through the stepwise injection of gelfoam microbeads into the uterine arteries, and then analyzed the associated Doppler velocimetric changes. Embolization of the uteroplacental circulation resulted in a dose-dependent decrease in blood flow, an increase in uterine vascular resistance, a dose-dependent attenuation of the pregnancy-related physiologic elevation in the diastolic flow velocity, an increase in PI,86 and the appearance of a diastolic notch.87 These findings suggest that elevated PI and the presence of a diastolic notch in the uterine artery velocity waveform indicate increased vascular resistance of the uteroplacental circulation.
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Correlation of Placental Bed Biopsies and Uterine Artery Doppler Velocity Waveforms
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Olofsson et al88 and Lin et al89 compared histologic findings of placental bed biopsies obtained at the time of cesarean section with uterine artery waveforms. They studied placental bed biopsies taken at cesarean section in 26 complicated (study group) and 29 uncomplicated (control group) pregnancies after performing Doppler velocimetry of the uterine arteries. Physiologic changes were absent in 77% (20 of 26) of the complicated pregnancies and present in all controls. Patients with abnormal placental bed biopsies were more likely to have elevated uterine artery PIs and abnormal pregnancy outcomes (pregnancy-induced hypertension or PIH, and SGA). Similar conclusions were reached by Lin et al,89 who studied 43 patients having Doppler examination of the uterine arteries within 7 days of delivery and found that 92% (12 of 13) of the patients with a uterine artery S/D ratio greater than or equal to 2.5 failed to show trophoblast migration into the myometrium. Patients with impaired trophoblast migration into the myometrium also delivered more prematurely (33.1 ± 2.7 versus 36.1 ± 2.2 weeks, P <.02) and had a higher rate of SGA fetuses (1290.2 ± 319.1 versus 1870.5 ± 523.1 g, P <.02).
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Prediction of Preeclampsia and SGA Fetuses
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Abnormal uterine artery Doppler flow velocity waveforms are characterized by elevated S/D ratios, RI, or PI, and the presence of a diastolic notch (see Figure 10-6). As discussed before, pregnancies complicated by preeclampsia, and to a lesser extent SGA fetuses, show evidence of impaired trophoblastic invasion of the myometrial portion of the spiral arteries.
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Therefore, many investigators have studied the potential role of uteroplacental Doppler to identify patients at risk for preeclampsia, SGA, preterm delivery, or adverse perinatal outcomes. Tables 10-3,10-4,10-5, and 10-6 summarize the results of such studies for high-risk (1987 to 1999; second trimester)14,90,91,92, and 93 or unselected populations (1986 to 1998; various gestational ages).94,95,96,97,98,99,100,101,102,103,104,105,106,107, and 108 In 14 studies,14,90,92,93, and 94,98,100,101, and 102,104,105,106,107, and 108 Doppler was considered effective in identifying a high-risk population for the development of preeclampsia and/or SGA; in 3,91,95,96 the results were inconclusive; and in 3,99,102,108 the results did not support a role for uteroplacental Doppler velocimetry as a screening test in pregnancy. Divergence among the studies is attributed to differences in patient selection and gestational age for screening, type of equipment used (CW, PW, or color Doppler), multiple definitions of abnormal flow velocity waveforms, different vessels examined, and heterogeneous outcome criteria.14,109 In addition, there was a wide variation in the number of patients studied, and also in the prevalence of adverse outcomes.
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Sensitivities for the detection of preeclampsia ranged from 25% to 100%. The sensitivity improved as gestational age approached 26 weeks, when the main uterine arteries were the vessels interrogated (rather than other vessels, such as arcuate arteries), and when a persistent diastolic notch was one of the criteria used for analysis.102 Positive predictive values (PPVs) for preeclampsia ranged from 2% to 50% in low-risk populations (see Table 10-5), and increased from 17% to 70% in high-risk populations (see Table 10-3). Sensitivities for the detection of SGA in low-risk populations ranged from 0% to 87%, whereas the PPV ranged from 0% to 54%.
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Albaiges et al performed one-stage screening for pregnancy complications (preeclampsia, fetal growth restriction, fetal death, and placental abruption) by utilizing Doppler assessment of the uterine arteries at 23 weeks' gestation in 1757 pregnancies.110 The sensitivities of increased mean uterine artery PI or bilateral notches were as follows: (1) 45% (95% CI = 32.2 to 57.4) for preeclampsia; (2) 90% (95% CI = 55.5 to 99.7) for preeclampsia that required delivery before 34 weeks; (3) 70% (95% CI = 34.8 to 93.3) of those whose infants had birth weights less than the 10th percentile and were delivered before 34 weeks; (4) 50% (95% CI = 18.8 to 81.3) of those with placental abruption that required emergency delivery; and (5) 83% (95% CI = 35.9 to 99.6) of fetal deaths. With regard to PPV, women at highest risk were those with both a high mean uterine artery PI and bilateral notches. These women had a 40% chance of developing preeclampsia, and a 45% chance for delivering infants weighing less than 10th percentile. Another important finding was the negative predictive value (NPV), which was more than 99% for adverse outcomes before 34 weeks, placental abruption, and fetal death.110 This suggests that women with normal uterine artery Doppler results are unlikely to develop preeclampsia, fetal growth restriction, or placental abruption, and therefore do not necessarily need antenatal follow-up that is as close as that required in women with abnormal uterine artery Doppler findings. In conclusion, a one-stage uterine artery screening program at 23 weeks identified most women who subsequently developed serious complications of impaired placentation associated with delivery before 34 weeks.
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A large, multicenter study in 7851 patients was conducted by the Fetal Medicine Foundation to screen for preeclampsia and fetal growth restriction by performing uterine artery Dopplers at 23 weeks.111 The mean PI of the 2 arteries was calculated and the presence of an early diastolic notch was noted. The sensitivity of mean uterine artery PI greater than 95th centile (false-positive rate or FPR, 5%) was (1) 69% for preeclampsia (with fetal growth restriction); (2) 24% for preeclampsia (without fetal growth restriction); and (3) 13% for fetal growth restriction (without preeclampsia). However, when delivery occurred before 32 weeks, the respective sensitivities increased to 93%, 80%, and 56%, respectively. The sensitivity of bilateral notches in predicting preeclampsia and/or fetal growth restriction was similar to that of increased PI, but the screen-positive rate with notches (9%) was much higher than that with increased PI (5%). Therefore, an important point is that the sensitivity for both preeclampsia and fetal growth restriction increases with the severity of the disease (as defined by earlier gestational age at delivery), or is inversely related to the gestational age at delivery. This study showed that a one-stage Doppler screening program at 23 weeks' gestation will identify most women who subsequently develop severe (and thus more clinically relevant) preeclampsia and/or fetal growth restriction.
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A recent study by Yu et al performed a prospective screening study for preeclampsia using uterine artery Doppler ultrasound in unselected, low-risk singleton pregnancies (32,000 women).112 There were 612 cases of preeclampsia, and 144 required early delivery (<34 weeks). When performing uterine artery Dopplers at 22 weeks' gestation either alone or in combination with maternal history, detection rates were 52% and 57%, respectively (FPR 10%). More importantly, Doppler was found to be particularly effective in screening for severe preeclampsia that necessitated iatrogenic delivery before 34 weeks, with a detection rate of 85% (FPR 10%).
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In 2008, a large, prospective, multicenter study (30,639 pregnancies) from the Fetal Medicine Foundation investigated the relationship between preeclampsia, SGA and gestational age at delivery, and the effect of this relationship on the prediction of preeclampsia via uterine artery Doppler imaging.113 Doppler of the uterine artery was performed at 22 to 24 weeks' gestation in unselected women with singleton pregnancies. In 2% of cases, women developed preeclampsia, and in this group there was an inverse significant association between gestational age at delivery and prevalence of SGA, and between gestational age at delivery and mean uterine artery PI and prevalence of mean uterine artery PI greater than 95th percentile. The mean uterine artery PI was greater than 95th percentile in (1) 77% of women who developed preeclampsia (requiring delivery before 34 weeks); (2) 36% of those delivering at 34 to 37 weeks; and (3) 22% of those delivering after 37 weeks. The respective percentages were higher for those with preeclampsia and SGA, but lower for those with SGA (but without preeclampsia). Similarly to others, the authors concluded that uterine artery Doppler assessment is more effective in identifying preeclampsia requiring preterm rather than term delivery.113
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Bower et al19 proposed a two-stage screening protocol for preeclampsia with uterine artery Doppler velocimetry performed at 18 to 22, and 24 weeks' gestation. In their study of 2058 low-risk patients, 16% (n = 329) had abnormal flow velocity waveforms (defined as the worst RI above the 95th percentile of reference range, or an early diastolic notch in either uterine artery) at 18 to 22 weeks. The presence of a persistent notch in the early diastolic component of the waveform at 24 weeks improved the predictive value of the test for preeclampsia (from 12% to 28%) and was associated with a 68-fold increased relative risk for the development of preeclampsia. Importantly, all women who delivered before 34 weeks because of severe preeclampsia had abnormal waveforms at both stages of screening. The authors concluded that preeclampsia can be predicted effectively by two-stage Doppler screening.
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Harrington et al108 examined the possibility of predicting preeclampsia and SGA at 12 to 16 weeks with transvaginal uterine and umbilical artery Doppler velocimetry. The parameters evaluated included the presence or absence of an early diastolic notch, vessel diameter, RI, PI, time-averaged mean velocity (TAV), maximum systolic velocity and volume flow in the right and left uterine arteries, and RI and PI in the umbilical arteries. The main outcome measures of the study were intrauterine death, birth weight, preeclampsia, and antepartum hemorrhage. Women who subsequently developed preeclampsia had significantly lower mean uterine artery TAV, lower volume flow, and elevated RI. The odds ratio (OR) for the development of preeclampsia in women with bilateral notches was 43.54 (95% CI = 5.84 to 324.73). These patients were also more likely to have SGA babies (OR = 8.61, 95% CI = 4.0 to 20.0), or deliver prematurely (OR = 2.38, 95% CI = 1.19 to 4.75).
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On the other hand, a large study conducted by Irion et al107 in a low-risk population, with similar inclusion criteria, Doppler examination technique, and outcome variables as the study of Bower et al,19 was not able to reproduce the results described earlier. The likelihood ratio for the development of preeclampsia in patients with a notch in the uterine arteries examined at 26 weeks was only 1.94 (95% CI = 1.14 to 3.31). The authors concluded that Doppler of the uteroplacental circulation did not fulfill the requirements for a screening test in unselected populations. However, they acknowledged that the likelihood ratios for the abnormal test confirmed the interest of this technique in selected patients at higher risk of obstetrical or perinatal complications (ie, those with risk factors for preeclampsia identified by medical history, second trimester arterial blood pressure, or a combination of biological tests, as well as those with risk factors for intrauterine growth retardation, and prematurity).
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Among the other studies that failed to show a benefit of uterine artery Doppler velocimetry as a screening test in pregnancy, the study by Newnham et al102 evaluated only the presence of SGA as an outcome variable. In the study of Hanretty et al,75 PIs obtained from subplacental vessels (radial or spiral arteries) were compared between a group of 32 normal pregnancies and a group of 32 pregnancies complicated by preeclampsia. All examinations were performed during the third trimester, and waveforms with the lowest resistance to flow were selected for analysis. No differences in PI were detected between the 2 groups. However, because of a sampling bias, these results are not surprising. Placental bed biopsies from patients with preeclampsia show areas lacking trophoblastic invasion scattered among areas with normal physiologic change.6 By selecting only those areas with the lowest resistance to flow, the possibility of sampling vessels with normal trophoblastic invasion but with abnormal placentation is increased.
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In 2004, Conde-Agudelo et al performed a World Health Organization (WHO) systematic review of screening tests for preeclampsia.114 Table 10-7 shows the results of updated meta-analyses of this review on the predictive accuracy of uterine artery Doppler velocimetry for preeclampsia.115 The majority were performed in the second trimester. Overall, it appears that the level of prediction of preeclampsia in low-risk populations is minimal to moderate, and in high-risk populations is minimal, regardless of the uterine artery Doppler indices used. In low-risk populations, the sensitivities and specificities of the uterine artery Doppler indices varied between 34% and 76%, and between 83% and 93%, respectively. The best predictors of preeclampsia were the presence of bilateral notches or an increased PI (positive likelihood ratio of 5). Although these indices appeared to have high specificity, this is at the expense of compromised sensitivity. For high-risk populations, all uterine artery Doppler indices had poor predictive ability, with positive likelihood ratios between 2.5 and 3.3, and negative likelihood ratios between 0.4 and 0.8. Combinations of notching and PI or RI did not improve the predictive accuracy of the single index.
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By contrast, Table 10-8 presents the predictive accuracies of uterine artery Doppler velocimetry for early onset preeclampsia (≤34 weeks' gestation).115 With the exception of 1 study,175 all were performed in the second trimester. Half of the studies reported positive likelihood ratios greater than 10, whereas the other half reported positive likelihood ratios between 5.0 and 10.0. Five studies reported negative likelihood ratios around 0.2. Therefore, regardless of the index or combinations of indices used, uterine artery Doppler velocimetry appears to be a moderate to good predictor for the development of preeclampsia appearing before 34 weeks' gestation.
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When evaluating uterine artery Doppler studies, an important point that has been frequently overlooked is the high NPV of the test.106,109 Studies in unselected populations have reported negative values ranging from 96% to 99%,94,95,96, and 97,101,102,104,105,108 and a substantial reduction in the risk of developing preeclampsia or delivering an SGA baby. Therefore, some have proposed that a normal uterine artery Doppler study at 24 weeks could serve to organize prenatal care by identifying a group of low-risk women who would be ideal candidates for community care during pregnancy.106,109 Kurdi et al106 performed uterine artery Doppler velocimetry in 946 low-risk women at 20 weeks to test this hypothesis, and found that 99% of the women with normal uterine artery Doppler flow velocity waveforms did not develop preeclampsia, and 96% did not deliver an SGA baby (birth weight below the 5th centile). Moreover, none of the women with normal Doppler studies required delivery before 37 weeks for preeclampsia or an SGA fetus. Indeed, in women with normal uterine artery Dopplers, the OR for developing any complication during pregnancy (defined as preeclampsia, placental abruption, delivery of an SGA baby below the 10th centile, or a pregnancy that resulted in stillbirth or a neonatal death) was 0.24 (95% CI = 0.17 to 0.34). The authors therefore concluded that these women form a "truly low-risk group, who should be suitable for community-led care, thereby enabling obstetricians to concentrate more time and energy on high-risk pregnancies."
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In conclusion, uterine artery Doppler velocimetry meets some of the criteria for the ideal predictive test for preeclampsia (simple, rapid, inexpensive, noninvasive, innocuous).115 However, there has been a wide range of sensitivity and PPVs reported in predicting preeclampsia and SGA fetuses. Some studies have shown that uterine artery Doppler is considered effective in identifying a high-risk population for the development of preeclampsia and/or SGA. However, recent and updated meta-analyses have found that the level of prediction of preeclampsia in low-risk populations is minimal to moderate, whereas for high-risk populations it is minimal, regardless of the Doppler indices used.115 Accordingly, the conclusion from the meta-analyses is that current evidence does not support the routine use of uterine artery Doppler for the prediction of preeclampsia in clinical settings.115 Importantly, however, because studies have shown that second trimester uterine artery Doppler is better (moderate to good) at predicting the development of preeclampsia before 34 weeks (early onset) (see Table 10-8), this method could be beneficial in the prediction of this condition. Finally, uterine artery Doppler screening has a high NPV (substantial reduction in the risk of developing preeclampsia or delivering an SGA baby).
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Prediction of Superimposed Preeclampsia in Patients With Chronic Hypertension
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The incidence of superimposed preeclampsia in pregnancies complicated by chronic hypertension ranges from 4.7% to 52%, depending on the severity of hypertension at the onset of pregnancy, and on the diagnostic criteria used.178 In this group of patients, superimposed preeclampsia is strongly associated with a worse perinatal outcome.178 It is no wonder, then, that uterine artery Doppler velocimetry has been investigated as a test to predict those who could develop superimposed preeclampsia among patients with chronic hypertension.179,180
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Caruso et al179 studied 42 women with chronic hypertension who had uterine artery Doppler velocimetry performed at 23 to 24 weeks. The prevalence of superimposed preeclampsia was 21%, and the lowest uterine artery waveform RI greater than 90th centile predicted this outcome with a sensitivity of 100%, specificity of 88%, PPV of 69%, and NPV of 100%. Patients with abnormal uterine artery Doppler velocimetry were also more likely to deliver a premature (30.5 ± 3.3 versus 38.3 ± 1.8 weeks, P = .0005) or low-birth-weight baby (1140 ± 651 versus 3034 ± 532 g, P = .0005), have a cesarean section for fetal distress (46% versus 0%, P = .0005), deliver a newborn with an Apgar score below 7 at 5 minutes (61.5% versus 0%, P = .0005), or have their baby admitted to the neonatal intensive care unit (69.2% versus 13.8%, P = .0005). Perinatal mortality rate was also higher for patients with abnormal uterine artery Doppler velocimetry (53.8% versus 0%, P = .0005).
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In another study of 78 chronic hypertensive patients, patients had uterine artery Dopplers performed at 24 weeks' gestation. Frusca et al180 found that the presence of bilateral diastolic notches in the uterine arteries was significantly more prevalent among patients who developed superimposed preeclampsia (23% versus 0%, P <.001), or delivered SGA babies (85% versus 3%, P <.001). Of interest was the low prevalence of superimposed preeclampsia, which was only 3.8%. With regards to this issue, the authors commented that, although this may be due to the small number of patients, it could also reflect a benefit of low-dose aspirin therapy (50 mg/day), which was prescribed to all patients from the 12th week of gestation until delivery.
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Smith et al recently performed a very large, screening study that examined maternal characteristics and uterine artery Doppler findings in over 30,000 women.181 They sought to relate the risk of antepartum stillbirth to uterine artery Doppler flow velocimetry at 22 to 24 weeks. There were 109 stillbirths, and these were divided into placental (due to abruption, preeclampsia, or growth restriction) or unexplained causes. The risk of placental stillbirth was increased among women with a mean PI in the top decile (adjusted hazard ratio 5.5, 95% CI = 2.8 to 10.6) and those with a bilateral notch (adjusted hazard ratio 3.9, 95% CI = 2.0 to 7.8). Placental stillbirths occurred at earlier gestational ages than unexplained stillbirths: median (interquartile range); 30 (26 to 36) versus 38 (36 to 40) weeks, P <.001. Abnormal uterine artery Doppler was a better predictor of the risk of stillbirth due to placental causes (than unexplained stillbirths). Consequently, abnormal uterine artery Doppler was a good predictor of stillbirth at extreme preterm gestations, but a poor predictor of stillbirth at term.