American Journal of Obstetrics and Gynecology (2005) 193, 1208–12

www.ajog.org

First trimester uterine artery Doppler abnormalitiespredict subsequent intrauterine growth restriction

Lorraine Dugoff, MD,a Anne M. Lynch, MD, MSPH,a Darleen Cioffi-Ragan, BA,a

John C. Hobbins, MD,a Lisa K. Schultz, RN,a Fergal D. Malone, MD,b

Mary E. D’Alton, MD,b for the FASTER Trial Research Consortium

Department of Obstetric and Gynecology, University of Colorado Health Sciences Center,a Denver, CO;Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons,b New York, NY

Received for publication March 1, 2005; revised June 2, 2005; accepted June 13, 2005

KEY WORDSFirst trimester

Uterine arteryDoppler

Intrauterine growth

restriction

Objective: This study was undertaken to evaluate the association between uterine artery Dopplervelocimetry performed between 10 and 14 weeks gestation and intrauterine growth restriction(IUGR).Study design: Uterine artery Doppler velocimetry data were collected on 1067 women enrolled in

the FASTER trial at the University of Colorado site. The data were analyzed by using univariateand multivariable logistic regression analysis.Results: The uterine artery mean resistance index (RI) for the entire cohort was equal on the right

and left sides (0.59 G 0.14). Of the 1067 women, 34.2% had unilateral or bilateral diastolicnotches, 1 notch was observed in 23.8%, and bilateral notches in 10.4%. Women with a highuterine artery mean RI (R75th percentile) were 5.5 times more likely to have IUGR (95% CI

1.6-18.7). There was no significant relationship between notching and IUGR.Conclusion: Elevated first trimester uterine artery mean RI is significantly associated with IUGR.� 2005 Mosby, Inc. All rights reserved.

Blood flow through the uteroplacental circulation canbe studied noninvasively with the use of Doppler ultra-sound. The impedance to flow in the uterine arteriesprogressively decreases during the first 2 trimesters ofnormal pregnancies. This observation has been attrib-uted to a direct effect of trophoblastic invasion on themusculoelastic coat of uterine spiral arteries.1 Placental

Funded by the National Institute of Child Health and Human

Development, Grant Number RO1 HD 38652.

Presented at the Twenty-Fifth Annual Meeting of the Society for

Maternal Fetal Medicine, Reno, Nev, February 7-12, 2005.

Reprints not available from the author.

0002-9378/$ - see front matter � 2005 Mosby, Inc. All rights reserved.

doi:10.1016/j.ajog.2005.06.054

pathology from pregnancies diagnosed with preeclamp-sia and intrauterine growth restriction (IUGR) showsfailure of the normal transition of maternal placentalarteries into low resistance vessels.2,3 A subsequenthistologic study on tissue obtained from women under-going elective first trimester pregnancy terminationconfirmed that Doppler resistance index (RI) wasinversely related the percentage of vessels demonstratingtrophoblastic invasion.4 This observation appears tosupport the thesis that a relationship between tropho-blastic invasion and RI can be demonstrated early inpregnancy, and gives credence to the possibility that thistechnique may prove useful in predicting adverse ob-stetric outcome, specifically IUGR, later in pregnancy.

Dugoff et al 1209

Previous studies have shown an association betweenincreased uterine artery impedance to flow measuredby Doppler velocimetry in the second trimester andsubsequent IUGR.5-8 It has also been previously demon-strated that the uterine artery RIs obtained transabdomi-nally at 10 to 14 weeks are repeatable and reproduciblemeasurements.9 These investigators showed that notch-ing was positively correlated with birth weight, whereasRI was negatively correlated.10 However, there are lim-ited data describing the relationship between uterineartery blood flow in early pregnancy and IUGR. Thegoal of this study was to evaluate the association betweenuterine artery Doppler velocimetry performed between10 and 14 weeks’ gestation and IUGR.

Material and methods

This is a study performed at a single site within theFASTER trial, a prospective multicenter observationalstudy whose goal was to compare the diagnostic per-formance of several first and second trimester screeningmarkers for Down syndrome that has been describedelsewhere.11 Women at the University of ColoradoHealth Sciences Center who consented to enroll in theFASTER trial between July 18, 2001, and December 3,2002, were asked if they would agree also to undergouterine artery Doppler investigation for this study. Thisprospective pilot study included all women enrolled inthe FASTER trial at the University of Colorado HealthSciences Center site who agreed to participate in thisstudy and for whom bilateral uterine artery RI andnotching data were obtained. Our analysis excluded allwomen carrying a fetus with a chromosomal or struc-tural abnormality or a genetic syndrome, women with apregnancy that resulted in a fetal demise at less than 24weeks’ gestation, those with a known congenital uterinemalformation, and those for whom pregnancy outcomedata were unavailable.

Ultrasound examinations were performed with theuse of a Voluson 730 and 730 MT (Medison, Cyprus,Calif) equipped with a 3.5-MHz curvilinear transabdo-minal probe. To perform the uterine artery Dopplerinterrogation, we followed a standard protocol that hasbeen used in the second trimester. Both uterine arterieswere identified with color Doppler at the point at whichthey appeared to cross the external iliac artery. Pulsewaved Doppler was used to obtain the waveforms. TheRI and the presence of an early diastolic notch wereassessed for both uterine arteries. All measurementswere performed by the same ultrasonographer andreviewed by a single investigator. A notch was consid-ered to be present when there was a clearly definedupturn of the flow velocity waveform at the beginning ofdiastole. The number of measurements obtained on eachside was determined by the sonographer. In the majorityof cases, 1 measurement was obtained on each side. In

the few cases in which more than 1 measurement wasobtained, we used the waveform that appeared to be thebest quality.

Relevant information on select maternal risk factors(maternal age, body mass index, nulliparity, prior pre-term birth, and gestational age at the time of the firsttrimester ultrasound) was included in this study. Thisinformation was collected at the time of enrollment inthe FASTER trial. Postdelivery follow-up was per-formed by telephone interview or medical record review.

The primary outcome we investigated was IUGR.IUGR was defined as birth weight less than the 10thpercentile for gestational age in Colorado womenusing the Lubchenco Colorado intrauterine growthcharts.12

Statistical analysis

The data were analyzed in SAS 8.2 (SAS Institute, Cary,NC). Initially, univariate analyses were conducted onthe primary explanatory variables (exposures) and selectmaternal risk factors to determine general descriptivestatistics. The mean RI for the right and left sides wasdetermined by calculating the sum of the RI values fromall the patients divided by the number of patients. Thiswas performed by using the data from each patient forthe right and then the left uterine artery. We alsodetermined the mean RI for each subject in the cohort(sum of the uterine artery RI for the right and left sidedivided by 2). We then looked at the distribution of themean uterine artery resistance for the entire cohort. Wedefined an elevated mean uterine artery RI as a valueabove the 75th, 90th, and 95th percentile for the entirecohort. An early diastolic notch was categorized aspresent or absent.

The relative risk (RR) was used as a measure ofassociation to test the relationship between these pri-mary explanatory variables and IUGR. The RR wasdefined as the cumulative incidence of IUGR amongmothers with the primary exposures divided by thecumulative incidence of IUGR among mothers withoutthe primary exposures. The incidence of IUGR in thesubjects with the exposures was compared with theincidence IUGR among women without the exposures.Measures of association between dichotomous variableswere tested by using the c2 or Fisher exact test. Statisticsare presented with 95% CI (P ! .05). We conductedmultivariable logistic regression analysis if there was asignificant relationship between either explanatory var-iable or the outcome from the univariate stage of theanalysis. In the multivariable logistic regression analysis,the odds ratio (OR) was used as an approximation ofthe RR and we estimated the OR of the primaryexplanatory variable for IUGR adjusted for othercovariates. Lastly, the performance characteristics for

1210 Dugoff et al

the prediction of IUGR by RI were calculated by usingsensitivity, specificity, and the positive and negativepredictive value.

Results

A total of 1066 women agreed to participate in thisstudy. Fifty-eight women were excluded from the studyfor the following reasons: fetal chromosomal abnormal-ity (n = 6), fetal structural abnormality (n = 12), fetalgenetic syndrome (n = 3), fetal demise less than 24weeks (n = 11), patient diagnosed with a congenitaluterine malformation (n = 1), and pregnancy outcomedata were unavailable (n = 25). Thus, a total of 1008cases were included in our final analysis.

Demographic characteristics of the women andpregnancy outcome are shown in Table I. Less than2% of the cohort had IUGR. Two of these pregnanciesresulted in a fetal demise with severe IUGR. The meanuterine artery RI in these cases of fetal death were 0.76and 0.78 (80th and 90th percentiles, respectively). Themost severe and earliest onset case of IUGR in ourcohort had a uterine artery mean RI of 0.82 (O95thpercentile) and required delivery at 25 weeks for fetalindications.

Table I Clinical Characteristics of the cohort (n = 1008)

Risk factors and outcomes

Mean maternal age G SD 33 G 5Nulliparity n (%) 502 (49.8)RaceWhite n (%) 857 (85.0)Black n (%) 25 (2.5)Hispanic n (%) 82 (8.1)Other n (%) 44 (4.4)

Body mass index (mean G SD) 23.3 G 4.0Cigarette smoker during currentpregnancy n (%)

39 (3.9)

Prior preterm birth n (%) 61 (6.1)Pregnancy outcomesIUGR 12 (1.2%)

Mean gestational age at delivery G SD 38.8 G 2Delivery!37 wks n (%) 77 (7.6)%32 wks n (%) 14 (1.4)Intrauterine fetal death n (%) 3 (0.3)

Table II Relative risk of uterine artery mean RI for IUGR

Percentile cut-offlevel for mean RI

Abovecut-off

Belowcut-off

RR(95% CI)

R75th (0.70*) 8/256 (3.1) 4/752 (0.5) 5.9 (1.8-19.3)R90th (0.78*) 4/106 (3.8) 8/902 (0.9) 4.3 (1.3-13.9)R95th (0.81*) 2/51 (3.9) 10/957 (1.0) 3.8 (0.8-16.7)

* Value of RI.

The mean uterine artery RI for the entire cohort ofpatients was equal on both sides (0.59 G 0.14). A totalof 663 women (65.8%) had no early diastolic notch onthe uterine artery waveform, 210 (20.8%) had a rightnotch only, 240 (23.8%) had a left notch only, and 105(10.4%) had bilateral notches.

The RR of mean uterine artery RI for IUGR atdifferent cut-off values is shown in Table II. Womenwhose mean RI was the 75th percentile or greater (0.70)were 5.9 times more likely to have a fetus affected byIUGR, whereas women whose mean RI was the 90thpercentile or greater (0.78) were 4.3 times more likely tohave an affected fetus. There was no significant associ-ation between notching (unilateral or bilateral) anddevelopment of IUGR.

The multivariable logistic regression analysis showingthe crude and adjusted ORs of mean RIR75th percentilefor IUGR is shown in Table III. Women who had amean RI R75th percentile were 5.5 times more likely tohave a growth-restricted infant when adjusted for ma-ternal age, body mass index, nulliparity, prior pretermbirth, and gestational age at the time of the first trimester

Table III Multivariable logistic regression analysis showingthe crude and adjusted ORs of mean RI R75th percentile forIUGR

OR

Risk factor Crude Adjusted 95% CI*

Mean RI R75thpercentile

6.0 5.5 1.6-18.7

Maternal age 1.2 1.2 1.0-1.4Body mass index 1.0 1.0 0.8-1.2Nulliparous 1.4 2.6 0.6-10.0Prior preterm birth 3.2 4.8 0.7-30.8Gestational ageat ultrasound

1.0 1.0 0.9-1.1

IUGR, Intrauterine growth restriction.

* For the adjusted OR.

Table IV Multivariable logistic regression analysis showingthe crude and adjusted ORs of mean RI for IUGR

OR

Risk factor Crude Adjusted 95% CI*

Mean RI 75th-90thpercentile

5.1 4.8 1.2-19.8

Mean RI O90thpercentile

7.3 6.4 1.6-26.7

Maternal age 1.2 1.2 1.0-1.3Body mass index 1.0 1.0 0.8-1.1Nulliparous 1.4 2.6 0.6-10.2Prior preterm birth 3.2 4.7 0.7-30.3Gestational ageat ultrasound

1.0 1.0 0.9-1.1

* For the adjusted OR.

Dugoff et al 1211

ultrasound was performed. Older women were also at asignificantly increased risk of having a growth-restrictedinfant. Table IV shows the results of a multivariablelogistic regression analysis using 2 categories of mean RI.This analysis demonstrates that the risk for IUGRincreases as the mean RI goes up. The performancecharacteristics for the prediction of IUGR by RI arelisted in Table V. These data suggest that we would beable to predict two thirds of IUGR cases by using the75th percentile RI as a cut-off.

Comment

In this pilot study we found that an elevated firsttrimester mean uterine artery RI was significantly asso-ciated with developing IUGR later in pregnancy. Thehighest quartile of our cohort contained 67% of thewomen who subsequently had IUGR develop. We didnot find any association between the presence of uterineartery notching and IUGR.

Three previous studies13-15 have examined the asso-ciation between first trimester uterine artery Dopplervelocimetry and IUGR. In 1995 a Dutch group14

showed that women with a high pulsatility index (PI),an alternative measurement of uterine artery impedance,had a 2.4-fold increase in the rate of IUGR. In 2001Martin et al13 also found that high PI was associatedwith the development of both IUGR and preeclampsia.Harrington et al15 reported similar findings in patientswho underwent measurement of uterine artery imped-ance between 12 and 16 weeks’ gestation. The predictiveimportance of notching was not clearly established byany of these studies.

Similar to Martin’s study, we found a relatively lowsensitivity for the mean uterine artery impedance cut-offof the 95th percentile or greater, though we measured RIrather than PI. However, we found that the sensitivitywas increased to 67% when the mean RI cut-off waslowered to the 75th percentile or greater. Although aspecificity of 75.1% (false-positive rate of 25%) might beless than optimal, we believe it would still be very usefulif we could identify two thirds of women in the firsttrimester of pregnancy who were destined to have a fetusaffected by IUGR. Identifying these women at such an

Table V Performance characteristics for IUGR

Mean RIcut-off

Sensitivity(%)

Specificity(%)

PPV(%)

NPV(%)

R75th (0.70) 66.7 75.1 3.1 99.5R90th (0.78) 33.3 89.8 3.8 99.1R95th (0.81) 16.7 95.1 3.9 99.0

IUGR, Intrauterine growth restriction; PPV, positive predictive value;

NPV, negative predictive value.

early stage could allow more aggressive monitoring oreven initiation of therapy.

The presence of notching has been suggested to beanother predictor of adverse fetal outcome. Part of thedifficulty in assessing this relationship relates to thesubjectivity inherent in the qualitative identification ofnotching. Martin et al13 observed notching in 75% of3324 women scanned in the first trimester, and dis-missed this criterion as unimportant because of itsfrequency. Notching is generally thought to be lesscommon with increasing gestational age, but was nev-ertheless observed in 55.6% of women scanned betweenweeks 12 and 16 in the study by Harrington et al.15

Again, the high prevalence of this finding would sug-gest that it would be unlikely to be of significantpredictive value for adverse obstetric outcome. Usingour criteria, we observed a 34.2% incidence of notchingbut found no association between notching and IUGR.On the basis of these data, we believe that the presenceof notching identified at the first trimester ultrasoundcannot be viewed as a clinically useful predictor of thedevelopment of IUGR, at least based on presentcriteria.

We had a relatively low incidence of adverse out-comes such as IUGR because of the low-risk populationenrolled in our study. This limited the statistical powerof our analysis to a large extent. The outcome we choseto evaluate, birth weight less than the 10th percentile forgestational age, included a spectrum of severity in termsof fetal growth impairment. The cases ranged fromhealthy infants delivered at term with birth weight lessthan the 10th percentile to infants with severe earlyonset growth restriction requiring early delivery, and in2 cases, resulting in fetal demise. Clearly, the severecases are the ones we are interested in identifying earlyin pregnancy, and the relatively low number of cases ofthis severity prevented us from stratifying our firsttrimester data to analyze this possibility. Present datasuggest that second trimester Doppler studies are effec-tive at predicting the most severe cases of IUGR andpreeclampsia.16,17 We speculate that, at the very least,first trimester Doppler screening may allow us to iden-tify those patients who may be at higher risk and shouldbe followed up with a second trimester scan.

Our obvious goal is to increase the sensitivity andpositive predictive value of Doppler velocimetry indetecting patients at risk of IUGR in the first trimester.We have previously reported on the association betweenlow maternal serum levels of pregnancy associatedplasma protein-A (PAPP-A) levels and low free betahuman chorionic gonadotropin levels at 10 3/7 weeksto 13 6/7 weeks and birth weight less than the 10thpercentile.18 In the future we hope to have sufficientcases to evaluate these multiple associations and todevelop a composite predictive panel that will increaseour sensitivity as well as positive predictive value.

1212 Dugoff et al

Acknowledgments

We acknowledge V. Faber, BA, and L. Sullivan, PhD,(DM-STAT, Inc, Medford, Mass) for their assistancewith coordination of data and outcome results.

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