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Individualized Risk Assessment for Adverse Pregnancy Outcome by Uterine Artery Doppler at 23 Weeks

From Harris Birthright Unit, King’s College Hospital, London; Department of Women’s Services, Queen Mary’s Hospital, Sidcup, Kent; and Cancer and Public Health Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Address reprint requests to: Christoph Lees, MD, MRCOG, Department of Obstetrics and Gynecology, Rosie Maternity Hospital, Addenbrooke’s NHS Trust, Hills Road, Cambridge, CB2 2QQ , United Kingdom; E-mail: cclees{at}compuserve.com.

	ABSTRACT

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OBJECTIVE: To provide individualized risk prediction of severe adverse pregnancy outcome based on uterine artery Doppler screening at 23 weeks.

METHODS: Color Doppler assessment of the uterine arteries was carried out in 5121 women attending for routine care at 23 weeks in two inner-city obstetric units. The mean uterine artery pulsatility index (PI) was calculated, and the likelihood ratios in relation to PI were generated for severe adverse outcome. This was defined as fetal death, placental abruption, and delivery before 34 weeks associated with preeclampsia and birth weight less than the 10th centile.

RESULTS: The likelihood of severe adverse pregnancy outcome increased quadratically with mean uterine artery PI. This relationship was not affected by maternal age, ethnicity, or parity. At a mean PI of 1.45, the 95th centile for our population, the likelihood ratio for severe adverse pregnancy outcome was 5. Cigarette smoking had an additional contribution to PI in predicting severe adverse outcome, roughly doubling the risk for a given PI.

CONCLUSION: The individualized risk of severe adverse pregnancy outcome can be determined by uterine artery Doppler screening at 23 weeks and knowledge of cigarette smoking history. Such individualized risk would allow ultrasound resources and clinical follow-up to be tailored to the pregnant woman for the most appropriate use of antenatal care.

Preeclampsia and fetal growth restriction (FGR) are often the consequence of impaired placentation. Preeclampsia is a leading cause of maternal mortality, and FGR is associated with a high perinatal mortality and both short- and long-term postnatal morbidity. Epidemiological studies have reported a link between low birth weight, diabetes mellitus, and cardiovascular disease, suggesting that the origins of adult disease lie in a hostile intrauterine environment.¹

Pregnancy is associated with physiologic changes in the uterine circulation resulting in a major increase in blood flow of about 40 mL per minute in the nonpregnant uterine artery to 400 mL per minute at term. This increase in blood flow is thought to be the consequence of a decrease in downstream resistance through trophoblast invasion of the maternal spiral arteries, a process beginning at conception and continuing until the end of the second trimester. Histologic studies of the placenta have shown that incomplete spiral artery invasion is associated with preeclampsia and FGR.²

The uteroplacental circulation can be assessed by Doppler ultrasound of the uterine arteries.³ Studies in the past two decades have established that in pregnancies failing to establish a low-resistance circulation, there is a substantial risk of complications such as preeclampsia, FGR, fetal death, and placental abruption.⁴ Most studies have defined an abnormal flow velocity waveform by showing an early diastolic notch in the waveform and/or an increase in the impedance index and thereby classified women artificially into high- and low-risk groups. However, trophoblast invasion and subsequent transformation of the spiral arteries into a low-impedance uteroplacental circulation is not an "all-or-nothing" phenomenon. The purpose of this study, therefore, is to estimate individual risk of severe adverse pregnancy outcome based on the pulsatility index (PI) of the uterine artery waveform at 23 weeks. Such individualization would allow a risk rather than an empirically based provision of antenatal care.

	MATERIALS AND METHODS

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Women who attend for routine antenatal care at King’s College Hospital, London, and Queen Mary’s Hospital, Sidcup, have Doppler examinations of the uterine arteries at 23 weeks’ gestation (Acuson Aspen, Acuson Co., Mountainview, CA, or Aloka SSD-1700, Aloka Co., Tokyo, Japan). The right and left uterine arteries are identified by color flow at the apparent crossover with the external iliac arteries, and pulsed-wave Doppler is used to obtain waveforms. When three similar, consecutive waveforms are obtained, the PI is measured and the mean uterine artery PI calculated. Women with normal uterine artery Doppler waveforms received routine antenatal care. Those with abnormal waveforms were followed up in a high-risk clinic commencing at 24 weeks.

Ultrasound findings and demographic data, including smoking status and ethnicity, are entered into a computer database (Fetal Database, Fetal Medicine Foundation, London) using a standard format data capture sheet. Smoking is defined as continued regular daily tobacco usage in pregnancy.

During an 18-month period at King’s College and Queen Mary’s Hospitals, women with singleton pregnancies who attended the ultrasound unit consecutively had uterine artery Doppler examinations at 22–25 (mean 23) weeks’ gestation. Doppler findings were recorded in a computerized patient database, and thermal waveform images were retained. A computer search was made of all patients with Doppler findings and complete data on demographic characteristics and pregnancy outcome.

Severe adverse outcomes were defined as preeclampsia associated with delivery before 34 weeks and birth weight less than the 10th centile for gestation⁵ associated with delivery before 34 weeks, fetal death, and placental abruption (defined as vaginal bleeding leading to emergency delivery and evidence of retroplacental clot at delivery). Preeclampsia was defined by blood pressure of 140/90 mmHg or greater on two occasions more than 6 hours apart, with proteinuria (minimum of 300 mg per 24 hours or dipstick testing of 300 mg/L) after 20 weeks in the absence of pre-existing hypertension.

Logistic regression was used to estimate unadjusted and adjusted odds ratios for each of the baseline variables and for mean PI (Stata Software, Stata Corp., College Station, TX). For mean PI, the results are presented as a likelihood ratio, defined as the posterior odds of disease divided by the prior odds of disease. Individual posterior odds of an adverse outcome were taken to be the fitted values of a multivariable logistic regression model, which included mean PI and smoking status as explanatory variables. Mean PI was included as a quantitative variable. The relationship between mean PI and log odds of an adverse outcome was nonlinear. A quadratic term was included in the model. The likelihood ratio was calculated as posterior odds of an adverse outcome divided by prior odds of an adverse outcome.

Sensitivity was defined as the percentage of women with a severe adverse outcome who had a positive test result, and specificity was defined as the percentage of women with a normal pregnancy outcome who had a negative test result. A receiver operating characteristic curve (sensitivity versus [1-specificity]) for severe adverse outcome related to mean PI was generated. The curve of smoothest fit was derived from a polynomial relationship in Microsoft Excel (Microsoft Corp., Redmond, WA).

	RESULTS

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The computer search identified 5121 women with complete data on pregnancy outcome; their demographic characteristics are shown in Table 1. Severe adverse outcome was found in 79 (1.5%); Table 2 details the individual outcomes. Univariable logistic regression analysis showed that mean PI, ethnicity, and smoking status were all significant risk factors for severe adverse outcome, whereas maternal age and parity were not (Table 3). The final model used had severe adverse outcome as the outcome variable, and mean PI, mean PI squared, and smoking status as explanatory variables. When mean PI was included in a multivariable logistic regression model with each of the baseline variables separately, only smoking status was significantly related to severe adverse outcome (Table 4). In a final model, which included both mean PI and smoking status as risk factors for an adverse outcome, smokers had their odds of having a severe adverse outcome multiplied by 2.18 (95% confidence interval [CI] 1.27, 3.74, P = .005) (Figure 1). The receiver operating characteristic curve for severe adverse outcome related to mean PI is shown in Figure 2.

View larger version (10K): [in this window] [in a new window]   Figure 1. Likelihood ratio for severe adverse outcome (vertical axis) relating to mean pulsatility index (horizontal axis). Smokers are represented by a thick block line, nonsmokers by a thin line. Lees. Uterine Doppler Risk Assessment. Obstet Gynecol 2001.

View larger version (8K): [in this window] [in a new window]   Figure 2. Receiver operating characteristic curve for severe adverse outcome and mean pulsatility index. Sensitivity (%) is plotted against 1-specificity (%). Lees. Uterine Doppler Risk Assessment. Obstet Gynecol 2001.

	DISCUSSION

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This uterine artery study differs from others in two important respects. First, we have considered only severe adverse pregnancy outcome, namely placental abruption, fetal death, and delivery before 34 weeks because of preeclampsia or FGR. Second, rather than define a high-risk population on the basis of uterine artery notches, we have treated uterine artery impedance as a continuous screening variable so as to make risk prediction specific to an individual patient.

We show a quantitative association between uterine artery resistance, measured by Doppler ultrasound at 23 weeks, and the likelihood of a woman developing a severe adverse pregnancy outcome. The data demonstrate a quadratic relationship between increasing mean uterine artery PI and the likelihood of subsequent severe adverse outcome. The 95th centile for mean PI in our population is 1.45; at this level, the likelihood ratio for severe adverse outcome is about 5 for nonsmokers and 10 for smokers.

Although African/Caribbean women have a significantly higher chance of severe adverse outcome compared with whites, this ethnic difference can be explained entirely through their higher mean uterine artery PI. In contrast, cigarette smoking doubles the risk of severe adverse outcome for a given mean uterine PI. The effect of cigarette smoking therefore appears independent of the development of the uteroplacental circulation. Previous studies have shown smoking before conception to be protective for preeclampsia,⁶ but smoking in pregnancy is known to be related to placental abruption and FGR.⁷ As our category of severe adverse outcome is a composite one that includes small for gestational age infants associated with delivery before 34 weeks, preeclampsia associated with delivery before 34 weeks, placental abruption, and fetal death, it is quite possible that smoking has a differential effect on individual outcomes. However, as these adverse outcomes are relatively infrequent, to ascertain these individual relationships would require separate analysis with greater numbers.

Controversy still exists over the value of uterine artery Doppler screening in antenatal care.⁴ There is no doubt that impaired trophoblast invasion of the spiral arteries is associated with subsequent uteroplacental insufficiency, and that uterine artery Doppler allows noninvasive assessment of the uteroplacental circulation. Disappointingly, the sensitivity of abnormal uterine artery Doppler for preeclampsia and delivery of small for gestational age infants ranges from 20% to 60% for a screen-positive rate of 5–10%.^8–12 However, the sensitivity for the severe, early onset complications of impaired placentation is 60–80%.^10,13

These data demonstrate the feasibility of defining with some precision an individual’s risk of severe adverse outcome relating to impaired trophoblast invasion. This requires a philosophical shift away from the concept of categorizing women simply as high- or low-risk pregnancies to a level of risk that can instead be quantified. Individualized risks would allow a more accurate assessment of the effectiveness of interventions in reducing adverse pregnancy outcome; for example, randomized studies of prophylactic agents have in the past recruited women with poorly defined and disparate levels of risk. Of particular clinical potential is using uterine artery risk assessment as a basis to determine a plan of antenatal care for each woman, allowing clinicians to make rational choices in directing the use and frequency of fetal and maternal monitoring resources.

	Footnotes

 
This study was funded by the Fetal Medicine Foundation, Charity No. 1037116.

The authors thank the sonographers at King’s College and Queen Mary’s Hospital for their support during this study.

PII S0029-7844(01)01474-0

Received January 16, 2001. Received in revised form May 18, 2001. Accepted May 24, 2001.

	REFERENCES

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8. Bower S, Bewley S, Campbell S. Improved prediction of preeclampsia by two stage screening of uterine arteries using the early diastolic notch and color Doppler imaging. Obstet Gynecol 1993;82:78–83.[Abstract/Free Full Text]

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10. Harrington K, Cooper D, Lees C, Hecher K, Campbell S. Doppler ultrasound of the uterine arteries: The importance of bilateral notching in the prediction of pre-eclampsia, placental abruption or delivery of a small-for-gestational-age baby. Ultrasound Obstet Gynecol 1996;7:182–8.[Medline]

11. North RA, Ferrier C, Long D, Townend K, Kincaid-Smith P. Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation. Obstet Gynecol 1994;83:378–86.[Abstract/Free Full Text]

12. Valensise H, Bezzeccheri V, Rizzo G, Tranquilli AL, Garzetti G, Romanini C. Doppler velocimetry of the uterine artery as a screening test for gestational hypertension. Ultrasound Obstet Gynecol 1993;3:18–22.[Medline]

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