Doppler in Obstetrics by Nicolaides, Rizzo, Hecker & Ximenes
The 11-14 weeks scan by Nicolaides, Sebire, Snijiders & Ximenes
The 18-23 weeks scan by Pilu, Nicolaides, Ximenes & Jeanty
 
INTRODUCTION
 
Impaired trophoblastic invasion of the maternal spiral arteries is associated with increased risk for subsequent development of intrauterine growth restriction, preeclampsia and placental abruption (see Chapter 4). A series of screening studies involving assessment of impedance to flow in the uterine arteries have examined the potential value of Doppler in identifying pregnancies at risk of the complications of impaired placentation (Figures 1–3).
 
STUDIES IN SELECTED POPULATIONS
Arduini et al. examined 60 women who had essential hypertension or renal disease or a previous pregnancy complicated by pregnancy-induced hypertension 1. They measured impedance to flow in the arcuate arteries at 18–20 weeks of gestation and defined as an abnormal result a resistance index of more than 0.57. They reported that this test identified 64% of pregnancies that subsequently developed pregnancy-induced hypertension (Table 1).
Figure 1: Insonation of the uterine artery at the crossover with the iliac artery.
Figure 2: Normal flow velocity waveform from the uterine artery at 24 weeks of gestation.
Figure 3: Flow velocity waveform from the uterine artery at 24 weeks of gestation in a pregnancy with impaired placentation; in early diastole there is a notch (yellow arrow) and in late diastole there is decreased flow (orange arrow).
In a similar study, Jacobson et al. examined 91 women who had chronic hypertension, history of pre-eclampsia or fetal loss and a variety of other medical conditions 2. They measured impedance to flow in the arcuate arteries at 24 weeks of gestation and defined as an abnormal result a resistance index of more than 0.57. Doppler signals could not be obtained in 8% of women and these pregnancies were considered to have abnormal test results. The sensitivity of the test for pregnancy-induced hypertension was 44% (Table 1). This study also examined prediction of intrauterine growth restriction (birth weight below the 10th centile for gestation), which was found in 18% of the cases and the sensitivity and positive predictive values were 71% and 33%, respectively.
 
Zimmermann et al. examined 172 women at high risk for hypertensive disorders of pregnancy or intrauterine growth restriction 3. They measured impedance to flow in the uterine arteries at 21–24 weeks of gestation and defined an abnormal result by a resistance index of more than 0.68. The prevalence of pre-eclampsia and/or intrauterine growth restriction was 18% and the sensitivity of increased impedance in the prediction of this complication was 56% (Table 1).
 
STUDIES IN UNSELECTED POPULATIONS
Several studies in unselected populations have examined the value of Doppler assessment of the uteroplacental circulation in the prediction of pre-eclampsia and/or intrauterine growth restriction. The main characteristics and results of the studies are summarized in Tables 2–4. The early studies were limited by the use of continuous wave Doppler, which is a blind investigation. However, recent studies have used color Doppler ultrasound to assess flow in the uterine artery at the point where it crosses the external iliac artery, which is a more reproducible examination.
Discrepant results between the studies may be the consequence of differences in Doppler technique for sampling and the definition of abnormal flow velocity waveform, differences in the populations examined (for example, the prevalence of pre-eclampsia varied from as low as 2% to as high as 24%), the gestational age at which women were studied, and different criteria for the diagnosis of pre-eclampsia and intrauterine growth restriction.
 
One-stage screening
 
Arcuate arteries
Campbell et al . examined the arcuate arteries in 126 pregnancies at 16–18 weeks of gestation 4. Subsequently, 12% of cases developed pre-eclampsia and 14% developed intrauterine growth restriction. The sensitivity of increased impedance (resistance index of more than 0.58) in the prediction of pre-eclampsia was 67% and, for intrauterine growth restriction, it was also 67%; the specificity was about 65% for both. In contrast, Hanretty et al. examined the arcuate arteries in 291 pregnancies at 26–30 weeks of gestation and found no difference in pregnancy outcome between those with normal and abnormal Doppler results 5.
Uterine and arcuate arteries
Bewley et al. calculated the average resistance index from the left and right uterine and arcuate arteries in 925 pregnancies at 16–24 weeks gestation 6. When the resistance index was greater than the 95th centile, there was a 10-fold increase in risk for a severe adverse outcome, defined by fetal death, placental abruption, intrauterine growth restriction or pre-eclampsia (prevalence 7%, sensitivity 21%, specificity 95%, positive predictive value 25%). However, the sensitivity of the test for pre-eclampsia or intrauterine growth restriction was only 24% and 19%, respectively with a specificity of about 95% for both.
 
Uterine arteries

Bower et al. examined the uterine arteries in 2058 pregnancies at 18–22 weeks 7. An abnormal result, defined by a resistance index above the 95th centile or the presence of an early diastolic notch in either of the two uterine arteries, was found in 16% of the pregnancies. The sensitivity of the test was 75% for pre-eclampsia and 46% for intrauterine growth restriction, and the specificity was 86% for both. This study highlighted the fact that abnormal Doppler results provide a better prediction of the more severe types of pregnancy complications. Thus, the sensitivity for mild pre-eclampsia was only 29%, but for moderate/severe disease the sensitivity was 82%. Similarly, the sensitivity for birth weight below the 10th centile was 38% and, for birth weight below the 5th centile, it was 46%.

Valensise et al. examined the uterine arteries in 272 primigravidas at 22 weeks of gestation 8. An abnormal result, defined by increased impedance (mean resistance index of more than 0.58) was found in 9.6% of patients. The sensitivity of the test in predicting pre-eclampsia was 89% and for intrauterine growth restriction it was 67%; the specificities were 93% and 95%, respectively. The sensitivity for predicting nonproteinuric pregnancy-induced hypertension was 50%.

North et al. examined the uterine arteries at 19–24 weeks of gestation in 457 nulliparous women and they found increased impedance (resistance index greater than 0.57 on the placental side) in 11% of cases 9. The sensitivity of the test for pre-eclampsia was 27%, and for intrauterine growth restriction it was 47%; the respective specificities were 90% and 91%. The test detected women with severe disease requiring delivery before 37 weeks with a sensitivity of 83% and specificity of 88%.

Chan et al. examined the uterine arteries at 20 weeks of gestation in 334 patients considered to be at medium risk for the development of pregnancy-induced hypertension 10. A screen-positive result, defined by a mean resistance index above the 90th centile and the presence of diastolic notches in both uterine arteries, was found in 4.2% of cases. The sensitivity of the test for pre-eclampsia was 22%, with a specificity of 97% and a positive predictive value of 35.7%.

Irion et al. examined the uterine arteries in 1159 nulliparous women at 26 weeks 11. Pre-eclampsia, intrauterine growth restriction and preterm delivery occurred in 4%, 11% and 7% of the pregnancies, respectively. At 26 weeks, increased impedance to flow (resistance index greater than 0.57) was present in 13% of cases and the sensitivity of the test was 26% for pre-eclampsia, 29% for growth restriction and 15% for preterm delivery.

Kurdi et al. examined the uterine arteries by color Doppler in 946 unselected women at 19–21 weeks of gestation 12. In 12.4% of cases, there were bilateral notches and, in this group, the odds ratio for developing pre-eclampsia was 12.8, and, for pre-eclampsia requiring delivery before 37 weeks, it was 52.6. When the uterine artery Doppler studies were normal, the odds ratio for developing pre-eclampsia was 0.11 and, for intrauterine growth restriction (birth weight below the 5th centile for gestation), it was 0.3. In women with bilateral notches and a mean resistance index  greater than 0.55, the sensitivities for pre-eclampsia and fetal growth restriction were 62% and 37%, respectively and, for these complications requiring delivery before 37 weeks, the sensitivities were 88% for both. It was concluded that women with normal uterine artery Doppler studies at 20 weeks constitute a group that have a low risk of developing obstetric complications related to uteroplacental insufficiency, whereas women with bilateral notches have an increased risk of the subsequent development of such complications, in particular those requiring delivery before term. Consequently, the results of Doppler studies of the uterine arteries at the time of the routine 20-week anomaly scan may be of use in determining the type and level of antenatal care that is offered to women.

 
Two-stage screening

Steel et al. examined the uterine arteries in 1014 nulliparous women by continuous wave Doppler at 18 weeks of gestation and, in those with increased impedance (resistance index greater than 0.58), the Doppler studies were repeated at 24 weeks 13. A screen-positive result (increased impedance at 24 weeks) was found in 12% of cases, and the sensitivity of the test for pre-eclampsia was 63% and for intrauterine growth restriction it was 43% (< 5th centile).

Bower et al. examined the uterine arteries in 2437 unselected women by continuous wave Doppler at 20 weeks of gestation 14. In those with increased impedance to flow (resistance index greater than the 95th centile or early diastolic notch in either of the two uterine arteries), the Doppler studies were repeated by color Doppler at 24 weeks. Persistently increased impedance was observed in 5.4% of the patients (compared to 16% at 20 weeks). It was reported that increased impedance provides good prediction of pre-eclampsia (but not of non-proteinuric pregnancy-induced hypertension). Furthermore, in terms of low birth weight, abnormal waveforms provide better prediction of severe (below the 3rd centile) rather than mild (below the 10th centile)intrauterine growth restriction (Table 5).

Harrington et al. examined the uterine arteries in 1233 unselected women by continuous wave Doppler at 20 weeks of gestation 15. In those with increased impedance (resistance index greater than the 95th centile or early diastolic notch in either of the uterine arteries), the Doppler studies were repeated by color Doppler at 24 weeks. Persistently increased impedance was observed in 8.9% of the patients. The sensitivity of the test for pre-eclampsia was 77%, and for intrauterine growth restriction it was 32%. Bilateral notching at 24 weeks was observed in 3.9% of patients; the sensitivity for pre-eclampsia was 55%, and for intrauterine growth restriction it was 22%. The respective sensitivities for those complications leading to delivery before 35 weeks were 81% and 58%.

Frusca et al. examined the uterine arteries in 419 nulliparous women by continuous wave Doppler at 20 weeks of gestation 16. In those with increased mean resistance index (greater than 0.58), the uterine arteries were examined by color Doppler at 24 weeks. Persistently high resistance was observed in 8.6% of the patients. The sensitivity of the test for pre-eclampsia was 50%, and for intrauterine growth restriction it was 43%. In the group with increased impedance at 20 weeks but normal results at 24 weeks, the prevalence of pregnancy complications was not increased compared to those with normal impedance at 20 weeks.
 
One-stage screening at 23 weeks
Albaiges et al. used color Doppler to examine the uterine arteries in 1757 singleton pregnancies attending for routine ultrasound examination at 23 weeks 17. Increased impedance was observed in 7.3% of patients, including 5.1% with mean pulsatility index of more than 1.45 and 4.4% with bilateral notches. Increased pulsatility index identified 35.3% of women who later developed pre-eclampsia and 80% with pre-eclampsia requiring delivery before 34 weeks; the respective values for bilateral notches were 32.3% and 80%. The sensitivity of increased pulsatility index (PI) for delivery of an infant with birth weight below the 10th centile was 20.9% and 70% for birth weight below the 10th centile delivering before 34 weeks; the respective values for bilateral notches were 13.3% and 50%.

These findings suggest that a one-stage color Doppler screening program at 23 weeks identifies most women who subsequently develop the serious complications of impaired placentation associated with delivery before 34 weeks. The screening results are similar if the high-risk group is defined either as those with increased PI or those with bilateral notches.
Randomized controlled trial
Davies et al. randomized 2600 unselected women to Doppler and non-Doppler groups 18. The Doppler studies were performed at 19–22 weeks and then at 32 weeks, unless the women were classified as being at high risk, in which case the Doppler studies were performed monthly. Continuous wave Doppler was used to obtain flow velocity waveforms in the lower lateral border of the uterus and an abnormal result was defined by the presence of an abnormal waveform bilaterally. There was a high frequency of pregnancy complications in women with abnormal uterine artery waveforms and it was concluded that abnormal waveforms are an indicator of subsequent fetal compromise. However, no improvement in neonatal outcome was demonstrated by routine Doppler screening.
PROPHYLAXIS STUDIES
 
Aspirin


Studies in the 1980s have suggested that low-dose aspirin in high-risk women reduces the prevalence of intrauterine growth restriction and pre-eclampsia 19–22. However, a series of randomized studies have shown no effect on the complications 23–27. In most studies, there were no adverse effects from aspirin, but in one study the incidence of antenatal, intrapartum and postpartum bleeding was increased 26. The results of the randomized studies have been criticized because the women examined were mostly at low risk for placental insufficiency.


Three randomized studies have examined the value of prophylactic aspirin in women considered to be at high risk of pre-eclampsia and intrauterine growth restriction because they had increased impedance in the uterine arteries (Table 6) 28–30.

McParland et al. carried out a two-stage Doppler screening study of the uterine arteries at 18–20 weeks and again at 24 weeks 28. Those with persistently high resistance index (more than 0.58) were randomized to aspirin (75 mg/day) versus placebo for the  remainder of the pregnancy. The difference between the aspirin and placebo groups in the frequency of pregnancy-induced hypertension (13% vs. 25%) did not achieve significance, but there were significant differences in the frequencies of pre-eclampsia (2% vs. 19%) and hypertension occurring before 37 weeks of gestation (0% vs. 17%). Fewer aspirin-treated than placebo-treated women had low birth weight babies (15% vs. 25%), but this difference was not significant. The only perinatal death in the aspirin group followed a cord accident during labor, whereas the three perinatal deaths in the placebo group were all due to severe hypertensive disease. No maternal or neonatal side-effects were observed in either group.

Bower et al. carried out a two-stage Doppler screening study of the uterine arteries at 18–22 weeks and again at 24 weeks 29. Those with persistently high resistance index or an early diastolic notch were randomized to aspirin (60 mg/day) or placebo. There was no significant difference in the incidence of intrauterine growth restriction (aspirin 26%, placebo 41%) or pre-eclampsia (aspirin 29%, placebo 41%), but severe pre-eclampsia (defined as a diastolic blood pressure of at least 110 mmHg with proteinuria of at least 300 mg/24 h or pre-eclampsia requiring treatment with intravenous antihypertensives and anticonvulsants) was significantly lower in the aspirin group (13%) than in the placebo group (38%). There was only one perinatal death and this occurred in a woman taking placebo. It was concluded that, in high risk pregnancy, low-dose aspirin commenced at 24 weeks may reduce the incidence of severe pre-eclampsia.

Morris et al. examined the uterine arteries by color Doppler at 18 weeks of gestation in 955 nulliparous women 30. An abnormal result (defined by a high resistance index and the presence of an ipsilateral early diastolic notch) was found in 186 women, and 102 of these agreed to randomization to either low-dose aspirin (100 mg/day) or placebo for the remainder of the pregnancy. Abnormal uterine artery flow velocity waveforms were associated with statistically significant increases in pre-eclampsia (11 vs. 4%), birth weight below the tenth centile (28 vs. 11%), and adverse pregnancy outcome (45 vs. 28%). Prophylactic aspirin therapy did not result in a significant reduction in pregnancy complications. It was concluded that, although abnormal uteroplacental resistance at 18 weeks of gestation is associated with a significant increase in adverse pregnancy outcome, low-dose aspirin does not reduce pregnancy complications in women with uteroplacental insufficiency.

Antioxidants
Impaired placental perfusion is thought to stimulate the release of pre-eclamptic factors that enter the maternal circulation and cause vascular endothelial dysfunction. Free oxygen radicals are possible promoters of maternal vascular dysfunction. It was, therefore, hypothesized that early supplementation with antioxidants may be effective in decreasing oxidative stress and improving vascular endothelial function, thereby preventing, or ameliorating, the course of pre-eclampsia 31.     

Chappellet al. identified 283 women as being at increased risk of pre-eclampsia by abnormal two-stage uterine artery Doppler analysis or a previous history of the disorder 32. The patients were randomly assigned to vitamin C (1000 mg/day) and vitamin E (400 IU/day) or to placebo at 16–22 weeks of gestation. In the intention-to-treat cohort, pre-eclampsia occurred significantly more commonly in the placebo group (17% of 142 women) than in the vitamin group (8% of 141). These findings suggest that supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease.

Multicenter trials are needed to show whether vitamin supplementation affects the occurrence of preeclampsia in low-risk women and to confirm these results in larger groups of high-risk women from different populations.
Nitric oxide donors

Nitric oxide, produced by the endothelium of blood vessels, is a potent vasodilator and inhibitor of platelet aggregation. Pre-eclampsia is associated with impaired production or function of nitric oxide and there is some evidence that treatment with the nitric oxide donor, glyceryl trinitrate, may reduce the prevalence or severity of this complication.

Ramsay et al. examined 15 women with increased impedance in the uterine arteries (mean resistance index of more than 0.6 and bilateral notches) at 24–26 weeks 33 . Infusion of glyceryl trinitrate was associated with a dose-dependent reduction in impedance to flow in the uterine arteries without a significant change in blood pressure, pulse rate or impedance in the umbilical artery or maternal carotid arteries. Grunewald et al. gave glyceryl trinitrate intravenously to women with severe pre-eclampsia and reported a decrease in maternal blood pressure and impedance in the umbilical artery, with no change in the impedance to flow in the uterine arteries 34. The effect of glyceryl trinitrate in this study may have been mediated by its placental transfer into the fetal vascular circuit, causing direct vasodilatation of the umbilical circulation. A similar effect has been shown using sublingual isosorbide dinitrate in healthy second-trimester pregnancy; umbilical and uterine artery impedances were lowered 35.

Lees et al. reported a randomized study of 40 women with abnormal uterine artery Doppler results at 24–26 weeks of gestation 36. Women were randomly allocated to receive transdermal glyceryl trinitrate 5-mg patches per day or equivalent placebo patches for 10 weeks or until delivery. The rates of pre-eclampsia, fetal growth restriction or preterm delivery were not significantly different in the two groups. Furthermore, there were no significant differences in maternal systolic and diastolic blood pressure, mean uterine artery resistance index and fetal umbilical and midde cerebral artery PIs between the groups.

CONCLUSIONS
  • Increased impedance to flow in the uterine arteries in both high-risk and low-risk pregnancies is associated with increased risk for subsequent development of pre-eclampsia and intrauterine growth restriction.
  • Women with normal impedance to flow in the uterine arteries constitute a group that have a low risk of developing obstetric complications related to uteroplacental insufficiency.
  • Increased impedance to flow in the uterine arteries at 24 weeks of gestation is found in about 5% of pregnancies attending for routine antenatal care. The prevalence of high impedance at 20 weeks is about 2–3 times higher than at 24 weeks.
  • Increased impedance to flow in the uterine arteries in pregnancies attending for routine antenatal care identifies about 50% of those that subsequently develop pre-eclampsia. Abnormal Doppler is better in predicting severe rather than mild pre-eclampsia. The sensitivity for severe pre-eclampsia is about 75%.
  • Increased impedance to flow in the uterine arteries in pregnancies attending for routine antenatal care identifies about 30% of those that subsequently develop intrauterine growth restriction. Abnormal Doppler is better in predicting severe (birth weight below the 3rd centile or growth restriction requiring delivery before 35 weeks) rather than mild growth restriction.
  • In pregnancies with increased impedance to flow in the uterine arteries, prophylactic treatment with low-dose aspirin or vitamins C and E may reduce the risk for subsequent development of pre-eclampsia.
 
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30. Morris JM, Fay RA, Ellwood DA, Cook CM, Devonald KJ. A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow. Obstet Gynecol 1996;87:74–8

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36. Lees C, Valensise H, Black R, Harrington K, Byers S, Romanini C, Campbell S. The efficacy and fetal-maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. Ultrasound Obstet Gynecol 1998;12:334–8

Doppler in Obstetrics
Copyright © 2002 by Kypros Nicolaides, Giuseppe Rizzo, Kurt Hecker and Renato Ximenes
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