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




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Dugoff et al                                                                                                       1209

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Dugoff et al                                                                                                              ...
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Arteria Uterina Primer Trimestre Y Rciu

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First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction, Lorraine Dugoff, ELSEVIER 2005

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  1. 1. American Journal of Obstetrics and Gynecology (2005) 193, 1208–12 www.ajog.org First trimester uterine artery Doppler abnormalities predict 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 WORDS Objective: This study was undertaken to evaluate the association between uterine artery Doppler First trimester velocimetry performed between 10 and 14 weeks gestation and intrauterine growth restriction Uterine artery (IUGR). Doppler Study design: Uterine artery Doppler velocimetry data were collected on 1067 women enrolled in Intrauterine growth the FASTER trial at the University of Colorado site. The data were analyzed by using univariate restriction and 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 diastolic notches, 1 notch was observed in 23.8%, and bilateral notches in 10.4%. Women with a high uterine 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. Ó 2005 Mosby, Inc. All rights reserved. Blood flow through the uteroplacental circulation can pathology from pregnancies diagnosed with preeclamp- be studied noninvasively with the use of Doppler ultra- sia and intrauterine growth restriction (IUGR) shows sound. The impedance to flow in the uterine arteries failure of the normal transition of maternal placental progressively decreases during the first 2 trimesters of arteries into low resistance vessels.2,3 A subsequent normal pregnancies. This observation has been attrib- histologic study on tissue obtained from women under- uted to a direct effect of trophoblastic invasion on the going elective first trimester pregnancy termination musculoelastic coat of uterine spiral arteries.1 Placental confirmed that Doppler resistance index (RI) was inversely related the percentage of vessels demonstrating trophoblastic invasion.4 This observation appears to support the thesis that a relationship between tropho- Funded by the National Institute of Child Health and Human blastic invasion and RI can be demonstrated early in Development, Grant Number RO1 HD 38652. Presented at the Twenty-Fifth Annual Meeting of the Society for pregnancy, and gives credence to the possibility that this Maternal Fetal Medicine, Reno, Nev, February 7-12, 2005. technique may prove useful in predicting adverse ob- Reprints not available from the author. stetric outcome, specifically IUGR, later in pregnancy. 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.06.054
  2. 2. Dugoff et al 1209 Previous studies have shown an association between the few cases in which more than 1 measurement was increased uterine artery impedance to flow measured obtained, we used the waveform that appeared to be the by Doppler velocimetry in the second trimester and best quality. subsequent IUGR.5-8 It has also been previously demon- Relevant information on select maternal risk factors strated that the uterine artery RIs obtained transabdomi- (maternal age, body mass index, nulliparity, prior pre- nally at 10 to 14 weeks are repeatable and reproducible term birth, and gestational age at the time of the first measurements.9 These investigators showed that notch- trimester ultrasound) was included in this study. This ing was positively correlated with birth weight, whereas information was collected at the time of enrollment in RI was negatively correlated.10 However, there are lim- the FASTER trial. Postdelivery follow-up was per- ited data describing the relationship between uterine formed by telephone interview or medical record review. artery blood flow in early pregnancy and IUGR. The The primary outcome we investigated was IUGR. goal of this study was to evaluate the association between IUGR was defined as birth weight less than the 10th uterine artery Doppler velocimetry performed between percentile for gestational age in Colorado women 10 and 14 weeks’ gestation and IUGR. using the Lubchenco Colorado intrauterine growth charts.12 Material and methods This is a study performed at a single site within the Statistical analysis FASTER trial, a prospective multicenter observational study whose goal was to compare the diagnostic per- The data were analyzed in SAS 8.2 (SAS Institute, Cary, formance of several first and second trimester screening NC). Initially, univariate analyses were conducted on markers for Down syndrome that has been described the primary explanatory variables (exposures) and select elsewhere.11 Women at the University of Colorado maternal risk factors to determine general descriptive Health Sciences Center who consented to enroll in the statistics. The mean RI for the right and left sides was FASTER trial between July 18, 2001, and December 3, determined by calculating the sum of the RI values from 2002, were asked if they would agree also to undergo all the patients divided by the number of patients. This uterine artery Doppler investigation for this study. This was performed by using the data from each patient for prospective pilot study included all women enrolled in the right and then the left uterine artery. We also the FASTER trial at the University of Colorado Health determined the mean RI for each subject in the cohort Sciences Center site who agreed to participate in this (sum of the uterine artery RI for the right and left side study and for whom bilateral uterine artery RI and divided by 2). We then looked at the distribution of the notching data were obtained. Our analysis excluded all mean uterine artery resistance for the entire cohort. We women carrying a fetus with a chromosomal or struc- defined an elevated mean uterine artery RI as a value tural abnormality or a genetic syndrome, women with a above the 75th, 90th, and 95th percentile for the entire pregnancy that resulted in a fetal demise at less than 24 cohort. An early diastolic notch was categorized as weeks’ gestation, those with a known congenital uterine present or absent. malformation, and those for whom pregnancy outcome The relative risk (RR) was used as a measure of data were unavailable. association to test the relationship between these pri- Ultrasound examinations were performed with the mary explanatory variables and IUGR. The RR was use of a Voluson 730 and 730 MT (Medison, Cyprus, defined as the cumulative incidence of IUGR among Calif) equipped with a 3.5-MHz curvilinear transabdo- mothers with the primary exposures divided by the minal probe. To perform the uterine artery Doppler cumulative incidence of IUGR among mothers without interrogation, we followed a standard protocol that has the primary exposures. The incidence of IUGR in the been used in the second trimester. Both uterine arteries subjects with the exposures was compared with the were identified with color Doppler at the point at which incidence IUGR among women without the exposures. they appeared to cross the external iliac artery. Pulse Measures of association between dichotomous variables waved Doppler was used to obtain the waveforms. The were tested by using the c2 or Fisher exact test. Statistics RI and the presence of an early diastolic notch were are presented with 95% CI (P ! .05). We conducted assessed for both uterine arteries. All measurements multivariable logistic regression analysis if there was a were performed by the same ultrasonographer and significant relationship between either explanatory var- reviewed by a single investigator. A notch was consid- iable or the outcome from the univariate stage of the ered to be present when there was a clearly defined analysis. In the multivariable logistic regression analysis, upturn of the flow velocity waveform at the beginning of the odds ratio (OR) was used as an approximation of diastole. The number of measurements obtained on each the RR and we estimated the OR of the primary side was determined by the sonographer. In the majority explanatory variable for IUGR adjusted for other of cases, 1 measurement was obtained on each side. In covariates. Lastly, the performance characteristics for
  3. 3. 1210 Dugoff et al Table I Clinical Characteristics of the cohort (n = 1008) Table III Multivariable logistic regression analysis showing Risk factors and outcomes the crude and adjusted ORs of mean RI R75th percentile for IUGR Mean maternal age G SD 33 G 5 Nulliparity n (%) 502 (49.8) OR Race Risk factor Crude Adjusted 95% CI* White n (%) 857 (85.0) Mean RI R75th 6.0 5.5 1.6-18.7 Black n (%) 25 (2.5) percentile Hispanic n (%) 82 (8.1) Maternal age 1.2 1.2 1.0-1.4 Other n (%) 44 (4.4) Body mass index 1.0 1.0 0.8-1.2 Body mass index (mean G SD) 23.3 G 4.0 Nulliparous 1.4 2.6 0.6-10.0 Cigarette smoker during current 39 (3.9) Prior preterm birth 3.2 4.8 0.7-30.8 pregnancy n (%) Gestational age 1.0 1.0 0.9-1.1 Prior preterm birth n (%) 61 (6.1) at ultrasound Pregnancy outcomes IUGR, Intrauterine growth restriction. IUGR 12 (1.2%) * For the adjusted OR. Mean gestational age at delivery G SD 38.8 G 2 Delivery !37 wks n (%) 77 (7.6) %32 wks n (%) 14 (1.4) Table IV Multivariable logistic regression analysis showing Intrauterine fetal death n (%) 3 (0.3) the crude and adjusted ORs of mean RI for IUGR OR Risk factor Crude Adjusted 95% CI* Table II Relative risk of uterine artery mean RI for IUGR Mean RI 75th-90th 5.1 4.8 1.2-19.8 Percentile cut-off Above Below RR percentile level for mean RI cut-off cut-off (95% CI) Mean RI O90th 7.3 6.4 1.6-26.7 R75th (0.70*) 8/256 (3.1) 4/752 (0.5) 5.9 (1.8-19.3) percentile R90th (0.78*) 4/106 (3.8) 8/902 (0.9) 4.3 (1.3-13.9) Maternal age 1.2 1.2 1.0-1.3 R95th (0.81*) 2/51 (3.9) 10/957 (1.0) 3.8 (0.8-16.7) Body mass index 1.0 1.0 0.8-1.1 * Value of RI. Nulliparous 1.4 2.6 0.6-10.2 Prior preterm birth 3.2 4.7 0.7-30.3 Gestational age 1.0 1.0 0.9-1.1 the prediction of IUGR by RI were calculated by using at ultrasound sensitivity, specificity, and the positive and negative * For the adjusted OR. predictive value. The mean uterine artery RI for the entire cohort of Results patients was equal on both sides (0.59 G 0.14). A total of 663 women (65.8%) had no early diastolic notch on A total of 1066 women agreed to participate in this the uterine artery waveform, 210 (20.8%) had a right study. Fifty-eight women were excluded from the study notch only, 240 (23.8%) had a left notch only, and 105 for the following reasons: fetal chromosomal abnormal- (10.4%) had bilateral notches. ity (n = 6), fetal structural abnormality (n = 12), fetal The RR of mean uterine artery RI for IUGR at genetic syndrome (n = 3), fetal demise less than 24 different cut-off values is shown in Table II. Women weeks (n = 11), patient diagnosed with a congenital whose mean RI was the 75th percentile or greater (0.70) uterine malformation (n = 1), and pregnancy outcome were 5.9 times more likely to have a fetus affected by data were unavailable (n = 25). Thus, a total of 1008 IUGR, whereas women whose mean RI was the 90th cases were included in our final analysis. percentile or greater (0.78) were 4.3 times more likely to Demographic characteristics of the women and have an affected fetus. There was no significant associ- pregnancy outcome are shown in Table I. Less than ation between notching (unilateral or bilateral) and 2% of the cohort had IUGR. Two of these pregnancies development of IUGR. resulted in a fetal demise with severe IUGR. The mean The multivariable logistic regression analysis showing uterine artery RI in these cases of fetal death were 0.76 the crude and adjusted ORs of mean RI R75th percentile and 0.78 (80th and 90th percentiles, respectively). The for IUGR is shown in Table III. Women who had a most severe and earliest onset case of IUGR in our mean RI R75th percentile were 5.5 times more likely to cohort had a uterine artery mean RI of 0.82 (O95th have a growth-restricted infant when adjusted for ma- percentile) and required delivery at 25 weeks for fetal ternal age, body mass index, nulliparity, prior preterm indications. birth, and gestational age at the time of the first trimester
  4. 4. Dugoff et al 1211 early stage could allow more aggressive monitoring or Table V Performance characteristics for IUGR even initiation of therapy. Mean RI Sensitivity Specificity PPV NPV The presence of notching has been suggested to be cut-off (%) (%) (%) (%) another predictor of adverse fetal outcome. Part of the R75th (0.70) 66.7 75.1 3.1 99.5 difficulty in assessing this relationship relates to the R90th (0.78) 33.3 89.8 3.8 99.1 subjectivity inherent in the qualitative identification of R95th (0.81) 16.7 95.1 3.9 99.0 notching. Martin et al13 observed notching in 75% of IUGR, Intrauterine growth restriction; PPV, positive predictive value; 3324 women scanned in the first trimester, and dis- NPV, negative predictive value. missed this criterion as unimportant because of its frequency. Notching is generally thought to be less common with increasing gestational age, but was nev- ultrasound was performed. Older women were also at a ertheless observed in 55.6% of women scanned between significantly increased risk of having a growth-restricted weeks 12 and 16 in the study by Harrington et al.15 infant. Table IV shows the results of a multivariable Again, the high prevalence of this finding would sug- logistic regression analysis using 2 categories of mean RI. gest that it would be unlikely to be of significant This analysis demonstrates that the risk for IUGR predictive value for adverse obstetric outcome. Using increases as the mean RI goes up. The performance our criteria, we observed a 34.2% incidence of notching characteristics for the prediction of IUGR by RI are but found no association between notching and IUGR. listed in Table V. These data suggest that we would be On the basis of these data, we believe that the presence able to predict two thirds of IUGR cases by using the of notching identified at the first trimester ultrasound 75th percentile RI as a cut-off. cannot be viewed as a clinically useful predictor of the development of IUGR, at least based on present criteria. Comment We had a relatively low incidence of adverse out- comes such as IUGR because of the low-risk population In this pilot study we found that an elevated first enrolled in our study. This limited the statistical power trimester mean uterine artery RI was significantly asso- of our analysis to a large extent. The outcome we chose ciated with developing IUGR later in pregnancy. The to evaluate, birth weight less than the 10th percentile for highest quartile of our cohort contained 67% of the gestational age, included a spectrum of severity in terms women who subsequently had IUGR develop. We did of fetal growth impairment. The cases ranged from not find any association between the presence of uterine healthy infants delivered at term with birth weight less artery notching and IUGR. than the 10th percentile to infants with severe early Three previous studies13-15 have examined the asso- onset growth restriction requiring early delivery, and in ciation between first trimester uterine artery Doppler 2 cases, resulting in fetal demise. Clearly, the severe velocimetry and IUGR. In 1995 a Dutch group14 cases are the ones we are interested in identifying early showed that women with a high pulsatility index (PI), in pregnancy, and the relatively low number of cases of an alternative measurement of uterine artery impedance, this severity prevented us from stratifying our first had a 2.4-fold increase in the rate of IUGR. In 2001 trimester data to analyze this possibility. Present data Martin et al13 also found that high PI was associated suggest that second trimester Doppler studies are effec- with the development of both IUGR and preeclampsia. tive at predicting the most severe cases of IUGR and Harrington et al15 reported similar findings in patients preeclampsia.16,17 We speculate that, at the very least, who underwent measurement of uterine artery imped- first trimester Doppler screening may allow us to iden- ance between 12 and 16 weeks’ gestation. The predictive tify those patients who may be at higher risk and should importance of notching was not clearly established by be followed up with a second trimester scan. any of these studies. Our obvious goal is to increase the sensitivity and Similar to Martin’s study, we found a relatively low positive predictive value of Doppler velocimetry in sensitivity for the mean uterine artery impedance cut-off detecting patients at risk of IUGR in the first trimester. of the 95th percentile or greater, though we measured RI We have previously reported on the association between rather than PI. However, we found that the sensitivity low maternal serum levels of pregnancy associated was increased to 67% when the mean RI cut-off was plasma protein-A (PAPP-A) levels and low free beta lowered to the 75th percentile or greater. Although a human chorionic gonadotropin levels at 10 3/7 weeks specificity of 75.1% (false-positive rate of 25%) might be to 13 6/7 weeks and birth weight less than the 10th less than optimal, we believe it would still be very useful percentile.18 In the future we hope to have sufficient if we could identify two thirds of women in the first cases to evaluate these multiple associations and to trimester of pregnancy who were destined to have a fetus develop a composite predictive panel that will increase affected by IUGR. Identifying these women at such an our sensitivity as well as positive predictive value.
  5. 5. 1212 Dugoff et al Acknowledgments 9. Hollis B, Mavrides E, Campbell S, Tekay A, Thilaganathan B. Reproducibility and repeatability of transabdominal uterine artery We acknowledge V. Faber, BA, and L. Sullivan, PhD, Doppler velocimetry between 10 and 14 weeks of gestation. Ultrasound Obstet Gynecol 2001;18:593-7. (DM-STAT, Inc, Medford, Mass) for their assistance 10. Hollis B, Prefumo F, Bhide A, Rao S, Thilaganathan B. First- with coordination of data and outcome results. trimester uterine artery blood flow and birth weight. Ultrasound Obstet Gynecol 2003;22:373-6. 11. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, References Bukowski R, et al. First and Second Trimester Evaluation of Risk for Fetal Aneuploidy (FASTER): principal results of the NICHD 1. Pijnenborg R, Dixon G, Robertson WB, Brosens I. Trophoblastic Multicenter Down Syndrome Screening Study. N Engl J Med invasion of human deciduas from 8 to 18 weeks of pregnancy. (in press). Placenta 1980;1:3-19. 12. Lubchenco LO, Hansman C, Boyd E. Intrauterine growth in 2. Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, length and head circumference as estimated from live births at Vercruysse L, et al. Placental bed spiral arteries in the hypertensive gestational ages from 26 to 42 weeks. Pediatrics 1966;37:403-8. disorders of pregnancy. BJOG 1991;98:648-55. 13. Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. 3. Aardema MW, Oosterhof H, Timmer A, van Rooy I, Aarnoudse Screening for pre-eclampsia and fetal growth restriction by uterine JG. Uterine artery Doppler flow and uteroplacental vascular artery Doppler at 11-14 weeks of gestation. Ultrasound Obstet pathology in normal pregnancies and pregnancies complicated by Gynecol 2001;18:583-6. pre-eclampsia and small for gestational age fetuses. Placenta 14. Van Den Elzen HJ, Cohen-Overbeek TE, Grobbee DE, Quartero 2001;22:405-11. RWP, Wladimeroff JW. Early uterine artery Doppler velocimetry 4. Prefumo F, Sebire NJ, Thilaganathan B. Decreased endovascular and the outcome of pregnancy in women aged 35 years and older. trophoblast invasion in first trimester pregnancies with high- Ultrasound Obstet Gynecol 1995;5:328-33. resistance uterine artery Doppler indices. Human Reprod 15. Harrington K, Goldfrad C, Carpenter RG, Campbell S. Trans- 2004;19:206-9. vaginal uterine and umbilical artery Doppler examination of 12-16 5. Bower S, Schuchter K, Campbell S. Doppler ultrasound screening weeks and the subsequent development of pre-eclampsia and as part of routine antenatal scanning: prediction of pre- intrauterine growth retardation. Ultrasound Obstet Gynecol eclampsia and intrauterine growth retardation. BJOG 1993; 1997;9:94-100. 100:989-94. 16. Papageorghiou AT, Yu CKH, Bindra R, Pandis G, Nicolaides 6. Irion O, Masse J, Forest JC, Moutquin JM. Prediction of pre- KH. Multicenter screening for pre-eclampsia and fetal growth eclampsia, low birthweight for gestation and prematurity by restriction by transvaginal uterine artery Doppler at 23 weeks of uterine artery blood flow velocity waveforms analysis in low risk gestation. Ultrasound Obstet Gynecol 2001;18:441-9. nulliparous women. BJOG 1998;105:422-9. 17. Bewley S, Cooper D, Campbell S. Doppler investigation of 7. Albaiges G, Missfelder-Lobos H, Parra M, Lees C, Cooper D, uteroplacental blood flow resistance in the second trimester: Nicolaides KH. Comparison of color Doppler uterine a screening study for pre-eclampsia and intrauterine growth artery indices in a population at high risk for adverse retardation. BJOG 1991;98:871-9. outcome at 24 weeks’ gestation. Ultrasound Obstet Gynecol 18. Dugoff L, Hobbins JC, Malone F, Porter TF, Luthy D, Comstock 2003;21:170-3. CH, et al. First- trimester maternal serum PAPP-A and free-beta 8. North RA, Ferrier C, Long D, Townsend K, Kincaid-Smith P. subunit human chorionic gonadotropin concentrations and nuchal Uterine artery Doppler flow velocity waveforms in the second translucency are associated with obstetric complications: a popu- trimester for the prediction of pre-eclampsia and fetal growth lation-based screening study (The FASTER Trial). Am J Obstet retardation. Obstet Gynecol 1994;83:378-86. Gynecol 2004;191:1446-51.

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