Article. Anthony O. Odibo, MD, Christopher Riddick, Emmanuelle Pare, MD, David M. Stamilio, MD, MSCE, George A. Macones, MD, MSCE

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1 Article Cerebroplacental Doppler Ratio and Adverse Perinatal Outcomes in Intrauterine Growth Restriction Evaluating the Impact of Using Gestational Age Specific Reference Values Anthony O. Odibo, MD, Christopher Riddick, Emmanuelle Pare, MD, David M. Stamilio, MD, MSCE, George A. Macones, MD, MSCE Objective. The purpose of this study was to compare the impact of using gestational age specific reference levels of the cerebroplacental Doppler ratio (CPR) with categorical threshold in the prediction of adverse perinatal outcomes in growth-restricted pregnancies. Methods. A retrospective cohort study of cases of intrauterine growth restriction over a 3-year period was conducted. The umbilical artery and middle cerebral artery pulsatility indices were converted to CPRs. The efficacy of using gestational age specific reference levels of CPRs in predicting adverse outcomes was compared with the use of a CPR of less than Adverse perinatal outcomes evaluated included cesarean delivery for nonreassuring fetal heart tones, umbilical artery ph less than 7.0, 5-minute Apgar scores less than 7.0, intraventricular hemorrhage greater than grade 2, periventricular leukomalacia, respiratory distress syndrome, and perinatal death. Results. Of 183 pregnancies meeting our inclusion criteria, there were 70 with at least 1 adverse outcome. With the use of a CPR ratio below the 5th percentile for gestational age, the sensitivity, specificity, and positive and negative predictive values for predicting an adverse outcome were 65%, 73%, 73%, and 65%, respectively, with an odds ratio (95% confidence interval) of 5.2 ( ; area under the receiver operating characteristic curve, 0.69). With a CPR threshold of less than 1.08, the sensitivity, specificity, and positive and negative predictive values were 72%, 62%, 68%, and 67%, with an odds ratio (95% confidence interval) of 4.2 ( ; area under the receiver operating characteristic curve, 0.67). Conclusions. An abnormal CPR is associated with adverse perinatal outcomes in growth-restricted fetuses. The accuracy of using gestational age specific reference levels was similar to that of using a categorical threshold. Key words: adverse outcomes; cerebral Doppler sonography; fetal growth restriction; umbilical artery Doppler sonography. Abbreviations CPR, cerebroplacental Doppler ratio; IUGR, intrauterine growth restriction; MCA, middle cerebral artery; ROC, receiver operating characteristic Received January 28, 2005, from the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania USA. Revision requested March 17, Revised manuscript accepted for publication April 6, Address correspondence to Anthony O. Odibo, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, 2000 Ravdin Courtyard, 3400 Spruce St, Philadelphia, PA USA. aodibo@obgyn.upenn.edu Intrauterine growth restriction (IUGR) is associated with adverse perinatal outcomes. The use of Doppler velocimetry has been shown to reliably predict these adverse outcomes. 1 Recent studies suggest that the cerebroplacental Doppler ratio (CPR), which is a ratio of the pulsatility indices of the middle cerebral artery (MCA) to the Doppler indices of the umbilical artery, is a better index for predicting adverse outcomes in IUGR when compared with using either the umbilical artery Doppler values or the MCA values alone. 2 6 However, the validity of the CPR appears to vary with gestational age. 7 In an attempt to correct this limitation, Baschat and Gembruch 7 developed a gestational age based nomogram for the CPR. To our knowledge, 2005 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2005; 24: /05/$3.50

2 Cerebroplacental Doppler Ratio in Intrauterine Growth Restriction that chart has not been validated by any study. Most of the previous studies on the efficacy of the CPR used categorical cutoff thresholds of the ratio. 3,5 The aim of this study was to determine the effect of using the gestational age specific reference levels of the CPR on the prediction of adverse perinatal outcomes in cases of IUGR compared with the use of categorical thresholds. Materials and Methods The study was a retrospective cohort study of cases of IUGR followed between October 2001 and July The study was approved by our Institutional Review Board. Intrauterine growth restriction was defined as estimated fetal weight below the 10th percentile. 8 We excluded all cases with congenital malformations, fetal aneuploidy, or twin-twin transfusion syndrome. Doppler examinations were performed with 3.5- to 5-MHz transducers (HDI 5000 SonoCT; Philips Medical Systems, Bothell, WA; and Voluson 730 Expert; GE Healthcare, Milwaukee, WI). Measurements were obtained from the middle section of the MCA and the umbilical artery Doppler signal from a free loop. Measurements were obtained during periods of fetal apnea, and the angle of insonation was maintained as close to 0 as possible when interrogating the MCA. The pulsatility index for the MCA and umbilical artery Doppler values were calculated. The measurements were performed weekly in cases with abnormal Doppler values or at the time of the next growth scan. The last measurements before delivery were used for our analyses. Cerebroplacental Doppler ratio measurements were not used for clinical management. In addition to Doppler evaluations, these cases with IUGR were monitored with twice-weekly nonstress tests and biophysical profiles. When a case with abnormal Doppler findings was identified, the patient was admitted and continuous monitoring was started. The IUGR fetuses were delivered because of either arrested fetal growth or abnormal biophysical test results. No fetus was delivered on the basis of Doppler findings. The perinatal outcomes evaluated included cesarean delivery for nonreassuring fetal heart tones (defined as either persistent poor variability or repetitive late decelerations during a nonstress test), umbilical artery ph less than 7.0, 5-minute Apgar scores less than 7.0, intraventricular hemorrhage greater than grade 2, periventricular leukomalacia, respiratory distress syndrome, and perinatal death. An abnormal CPR was defined as a CPR of less than 1.08 or a CPR below the 5th percentile for gestational age on the basis of the nomogram by Baschat and Gembruch. 7 The sensitivity, specificity, and predictive values for predicting a composite of these adverse outcomes were calculated. Using logistic regression diagnostics, the odds ratios and the areas under the receiver operating characteristic (ROC) curves for the association with perinatal outcomes by both methods were computed. In a further analysis, we evaluated the use of the 2 definitions of an abnormal CPR for the prediction of adverse outcomes in IUGR below the 5th percentile. We also performed a subanalysis to evaluate the impact of limiting our analyses to IUGR at gestational ages less than 34 weeks. This was to address the suggestion that, at about 34 weeks, the predictive value of the CPR decreases. 6 The duration from the last Doppler evaluation to delivery in cases with normal and abnormal CPRs were compared by Kaplan-Meier survival curves and their significance was evaluated using the log rank test. All statistical analyses were performed with Stata version 8.0 (StataCorp, College Station, TX). Results We identified 183 patients from our perinatal database with complete information on Doppler evaluation over the study period. The demographic details of the study population are shown in Table 1. There were 155 cases of IUGR below the 5th percentile for gestational age. Fifty-one cases of IUGR below the 10th percentile and 36 cases below the 5th percentile were less than 34 weeks gestation at delivery. The indications for admission to the neonatal intensive care unit included neonatal hypoglycemia, respiratory distress syndrome, suspected neonatal sepsis, extreme prematurity (delivery at <32 weeks) and cord blood arterial ph less than 7.0. The mean interval ± SD from the last Doppler evaluation to delivery for the study population was 9.8 ± 9.7 days, with a range of 0 to 32 days. Table 2 shows the adverse perinatal outcomes seen in the study population. Because the incidence of each adverse outcome was low, we used a composite of the presence of at least 1 adverse perinatal outcome for our primary analysis. At least 1 adverse perinatal outcome was present in 70 (38%) of these IUGR cases J Ultrasound Med 2005; 24:

3 Odibo et al When used for the prediction of adverse perinatal outcomes, absent or reversed end-diastolic Doppler flow of the umbilical artery (used as a categorical variable) had sensitivity, specificity, and positive and negative predictive values of 34%, 93%, 75%, and 70%, respectively. The area under the ROC curve of absent or reversed end-diastolic Doppler flow of the umbilical artery for predicting an adverse perinatal outcome was 70%. An abnormal MCA had sensitivity, specificity, and positive and negative predictive values of 35%, 56%, 35%, and 56% for predicting an adverse perinatal outcome (area under the ROC curve, 48%). The screening efficiency of the CPR in the prediction of adverse perinatal outcomes is shown in Table 3 for cases of IUGR below the 10th and 5th percentiles, respectively. The sensitivity for predicting adverse outcomes using the 2 CPR cutoffs were lower for the subgroup of IUGR below the 5th percentile compared with the primary analysis including all cases of IUGR. However, the specificity was similar. The efficiency of using the CPR of less than 1.08 and CPR below the 5th percentile for gestational age was similar, with odds ratios (95% confidence intervals) of 4.2 ( ) and 5.2 ( ), respectively, for IUGR below the 10th percentile and 3.8 ( ) and 3.9 ( ) for IUGR below the 5th percentile. When the analysis was limited to cases of IUGR at less than 34 weeks, the sensitivity for the CPR with the use of the 2 definitions for abnormality was markedly improved (Table 4). With the exception of a CPR of less than 1.08 (for IUGR <10th percentile), the specificity of CPR was similar to that for the total cases of IUGR in the subgroup of less than 34 weeks. The Kaplan-Meier curves showing the relationship between the interval from the last Doppler evaluation to delivery and the proportion of cases with adverse outcomes for cases with normal and abnormal CPRs are shown in Figures 1 and 2. The curves show higher proportions of adverse outcomes in cases with an abnormal CPR at the earlier intervals from Doppler evaluation to delivery, but as the interval increases, the proportion with adverse outcomes becomes higher in the cases with a normal CPR. This relationship was statistically significant according to the log rank test for an abnormal CPR defined with the use of a CPR below the 5th percentile, with a trend toward being significant for a CPR of less than Table 1. Demographics of the Study Population (n = 183) Demographic Discussion Value Mean maternal age ± SD, y 26.6 ± 6.8 Race, n (%) White 48 (26) Black 123 (67) Asian 8 (5) Other 4 (2) Mean Gestational age at delivery ± SD, wk 35.6 ± 3.6 Mean birth weight ± SD, g 1770 ± 575 NICU admissions, n (%) 100 (55) NICU indicates neonatal intensive care unit. The CPR incorporates data of both placental status (umbilical artery) and fetal response (MCA) in the prediction of adverse outcomes. In this study, comparing the use of gestational age specific thresholds with categorical thresholds of the CPR, we found similar efficiency in the prediction of adverse perinatal outcomes using both methods. This implies that perinatal centers can use either method in the evaluation of cases of IUGR. The efficiency of using the CPR found in this study was, however, modest. The area under the ROC curves with the 2 methods of evaluating the CPR were 67% and 69%, respectively. Therefore, given 2 cases of IUGR, the CPR has less than a 70% chance of correctly predicting which case will have an adverse perinatal outcome. From an epidemiologic standpoint, the CPR would not be considered a highly efficient predictor of adverse perinatal outcomes. An ideal test should have an area under the curve close to 100%. 9 However, compared with either umbilical artery Doppler or MCA indices, the CPR was associated with improved sensitivity in Table 2. Adverse Perinatal Outcomes Observed in the Study Population (n = 183) Outcome n (%) Cesarean delivery for nonreassuring 32 (17) fetal heart tone Arterial ph < (6) Apgar score at 5 min <7 10 (6) Necrotizing enterocolitis 5 (3) Intraventricular hemorrhage >grade 2 5 (3) Respiratory distress syndrome 30 (16) Periventricular leukomalacia 1 (<1) Perinatal death 11 (6) J Ultrasound Med 2005; 24:

4 Cerebroplacental Doppler Ratio in Intrauterine Growth Restriction Table 3. Screening Efficiency of Using the CPR in Prediction of Adverse Perinatal Outcomes in Cases With IUGR Test n Sensitivity, % Specificity, % PPV, % NPV, % AUC, % CPR <1.08 (IUGR <10%) CPR <1.08 (IUGR <5 %) CPR <5th percentile (IUGR <10%) CPR <5th percentile (IUGR <5%) AUC indicates area under the ROC curve; NPV, negative predictive value; and PPV, positive predictive value. Table 4. Screening Efficiency of Using the CPR in Prediction of Adverse Perinatal Outcomes in Cases With IUGR at Less Than 34 Weeks Gestation Test n Sensitivity, % Specificity, % PPV, % NPV, % AUC, % CPR <1.08 (IUGR <10%) CPR <1.08 (IUGR <5%) CPR <5th percentile (IUGR <10%) CPR <5th percentile (IUGR <5%) AUC indicates area under the ROC curve; NPV, negative predictive value; and PPV, positive predictive value. predicting an adverse perinatal outcome. The specificity of the CPR was, however, much lower than that of umbilical artery Doppler findings in this study. The latter result suggests that, although the CPR may increase prediction of adverse perinatal outcomes, absent or reversed umbilical artery Doppler flow may be more useful in avoiding unnecessary interventions in cases of IUGR. This study found a similar performance in predicting adverse outcomes by abnormal CPR in the subgroup with more severe IUGR (<5th percentile). The sensitivity of the CPR in cases with IUGR at less than 34 weeks was higher than for the overall study population. In addition, the area under the ROC curve was consistently higher for CPR in cases of IUGR at less than 34 weeks. This is consistent with findings by Bahado-Singh et al, 6 who reported the CPR to be most predictive of adverse outcomes in cases at less than 34 weeks. The specificity of CPR at gestational ages of less than 34 weeks was, however, still suboptimal. This is an important limitation of the CPR identified by this study because interventions based on CPR in these preterm growth-restricted pregnancies could have drastic consequences. The findings based on the Kaplan-Meier curves could be due to early interventions in cases in which the clinician was already aware of the abnormal Doppler findings. An alternative explanation could be that abnormal CPR is highly correlated with other antepartum testing parameters such as the biophysical profile, which were used to time the delivery of these patients. Future studies addressing such hypothesis could be highly informative. The sensitivity of the CPR from our study is similar to those previously reported for predicting adverse perinatal outcomes in IUGR. 3,6 In a study by Gramellini et al, 3 a CPR of less than 1.08 had a sensitivity of 68% for predicting adverse perinatal outcomes in IUGR. Bahado-Singh et al 6 reported a sensitivity of 63% for predicting adverse outcomes using a CPR transformed to multiples of the median for each gestational age. However, the specificity reported in our study is lower than in these previous studies. 3,6 The reason for this discrepancy is uncertain, but difference in patient populations is a likely reason. Because we are dealing with a high-risk population, maximizing the sensitivity of a screening test is an ideal goal. However, this must be balanced with a reasonable specificity to avoid unnecessary interventions, such as premature delivery. The CPR has been shown to be a good predictor of the fetal oxygenation status at birth and can be used to identify pregnancies that are at risk for adverse outcomes. 3,5,6 Animal studies suggest that the CPR is superior to the MCA pulsatility index in predicting adverse perinatal outcomes because it reflects acute changes more accurately. 2,7,10 Therefore, accurate measurement of the CPR is important. Baschat and Gembruch 7 reported a gestational age based CPR nomogram. The aim of the latter study was to present a uniform method of evaluating the CPR. Our findings externally validate their nomogram and confirm that the CPR is more effective in predicting adverse perinatal outcomes compared with the umbilical artery 1226 J Ultrasound Med 2005; 24:

5 Odibo et al Figure 1. Relationship between abnormal CPR <5th percentile, days from last Doppler evaluation to delivery, and adverse perinatal outcomes. Doppler or MCA index only. However, we also found no significant difference between using a categorical cutoff of CPR less than 1.08 or below the 5th percentile. Our study has some limitations, including a retrospective design with the possibility of hidden biases. Our sample size was small, with relatively small numbers of adverse perinatal outcomes. The latter prompted us to use a composite of adverse perinatal outcomes for our primary analysis. However, the fact that our findings are comparable with previous reports supports the robustness of our conclusions. The emphasis of the study was the sensitivity of the CPR, and post hoc power analysis revealed that, to detect an increase in the sensitivity of the CPR in predicting adverse perinatal outcomes to 80%, with an intended confidence interval around that estimate of ±15%, we would need to enroll 27 Figure 2. Relationship between abnormal CPR <1.08, days from last Doppler evaluation to delivery, and adverse perinatal outcomes. women carrying fetuses with adverse perinatal outcomes. Therefore, our study sample size had sufficient statistical power to detect a difference in prediction of cesarean delivery for nonreassuring fetal heart tones and respiratory distress and certainly for the composite outcome of adverse perinatal outcomes with the use of the 2 methods of calculating the CPR. In conclusion, our study found the CPR to be modestly predictive of adverse perinatal outcomes in cases of IUGR, and the use of a gestational age specific threshold and categorical cutoffs of the CPR were both associated with similar efficiency. Larger studies are needed to corroborate our findings. References 1. Alfrevic Z, Neilson JP. Doppler ultrasonography in high-risk pregnancies: systematic review with metaanalysis. Am J Obstet Gynecol 1995; 172: Arbeille P, Maulik D, Fignon A, et al. Assessment of the fetal po 2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol 1995; 21: Gramellini D, Folli MC, Raboni S, Vadora E, Merialdi A. Cerebral-umbilical Doppler ratio as a predictor of adverse perinatal outcome. Obstet Gynecol 1992; 74: Arias F. Accuracy of the middle-cerebral-to-umbilical-artery resistance index ratios in the prediction of neonatal outcome in patients at high risk for fetal and neonatal complications. Am J Obstet Gynecol 1994; 171: Devine PA, Bracero LA, Lusikiewicz A, Evans R, Womack S, Byrne DW. Middle cerebral to umbilical artery Doppler ratio in Post-date pregnancies. Obstet Gynecol 1994; 84: Bahado-Singh RO, Kovanci E, Jeffres A, et al. The Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet Gynecol 1999; 180: Baschat AA, Gembruch U. The cerebroplacental Doppler ratio revisited. Ultrasound Obstet Gynecol 2003; 21: Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996; 87: J Ultrasound Med 2005; 24:

6 Cerebroplacental Doppler Ratio in Intrauterine Growth Restriction 9. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982; 143: Harrington K, Thompson MO, Carpenter RG, Nguyen M, Campbell S. Doppler of the fetal circulation in pregnancies complicated by preeclampsia or delivery of a small for gestational age baby, 2: longitudinal analysis. Br J Obstet Gynaecol 1999; 106: J Ultrasound Med 2005; 24: