Ratio of middle cerebral to umbilical artery blood velocity in preeclamptic & hypertensive women in the prediction of poor perinatal outcome

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1 Indian J Med Res 120, July 2004, pp Ratio of middle cerebral to umbilical artery blood velocity in preeclamptic & hypertensive women in the prediction of poor perinatal outcome Serap Yalti, Özay Oral, Birgül Gürbüz, Selçuk Özden & Feyruz Atar Zeynep Kamil Women & Children Education & Research Hospital, Department of High Risk Pregnancy, Istanbul, Turkey Received July 23, 2003 Background & objectives: Doppler velocimetry studies of placental and foetal circulation can provide important information regarding foetal well-being providing an opportunity to improve foetal outcome. The present study was undertaken to evaluate the role of middle cerebral to umbilical artery blood velocity waveform's systolic/diastolic ratio (MCA/UA) and biophysical profile as a predictor of perinatal outcome in hypertensive and preeclamptic pregnant women during the late third trimester. Methods: Fifty preeclamptic pregnant women selected randomly in the last three weeks of the third trimester were stratified into two groups based on the MCA/UA ratio. All women were evaluated by foetal biophysical profile scoring. Thirty four women with foetal MCA/UA ratios > 1 and 16 with 1 were recruited in groups A and B respectively. The results of the ratio, and biophysical profile were evaluated with respect to the outcome of the infants and adverse perinatal outcome, defined as perinatal death, foetal cord blood gas analyses, cesarean delivery for foetal distress, admission to the neonatal intensive care unit, days in the neonatal intensive care unit (NICU) or low Apgar score. Results: Rate of cesarean delivery was significantly (P<0.001) higher in group B than group A. There was a statistically significant increase in perinatal morbidity in B group. Apgar scores at 1 and 5 min were found to be lower in group B than group A. Umbilical cord blood partial oxygen pressure (po 2 ), partial carbon dioxide pressure (pco 2 ) was not different in the two groups; whereas, ph was lower in group B. In group A two neonates (5.9%) and in group B 12 neonates (75%) required admission in neonatal intensive care unit. Best cut-off levels of MCA, MCA/UA ratios were found to be 3 and 1, respectively. Interpretation & conclusion: The MCA/UA was valuable for predicting the outcome of preeclamptic and hypertensive pregnancies. When the ratio was <1, foetal prognosis was poor. Key words Foetal prognosis - middle cerebral artery - umbilical artery Doppler ultrasound velosimetry of uteroplacental, umbilical and foetal vessels provides important information on the haemodynamics of the vascular area under study 1. In experienced hands, Doppler screening of the foetal middle artery waveforms during labour can be useful in the evaluation of intrapartum hypoxia in complicated pregnancies 2. Several studies have reported higher sensitivities and specificities for middle cerebral artery/umbilical artery (MCA/UA) Doppler ratio compared with umbilical velocimetry alone for prediction of foetal prognosis 3-6. MCA/UA ratio reflects not only the circulatory insufficiency of the umbilical velocimetry of the placenta manifested by alterations in the umbilical S/D ratio 44

2 (ratio of peak systolic blood flow velocity to diastolic velocity) but also the adaptative changes resulting in modifications of the middle cerebral S/D ratio 3. MCA/UA ratio is a good predictor of neonatal outcome, and could be used to identify foetuses at risk of morbidity and mortality. In this study we evaluated the predicting value of umbilical artery, the MCA/UA ratio, and the cerebral index for foetal prognosis in the late third trimester in hypertensive, preeclamptic women. Material & Methods A total of 50 high risk women in the third trimester of pregnancy were included from those referred to the antenatal clinic at Zeynep Kamil Women's and Children Diseases Education and Research Hospital, Istanbul, Turkey after obtaining informed constent. Approval for the study was obtained from the ethics committee of Institution. Due to the extended scope of our exclusion criteria, the sample size was small. The gestational age of all women was confirmed, either by menstrual dates or by second trimester ultrasonography. Preeclampsia was diagnosed in those women who were normotensive during early pregnancy, but later demonstrated elevated blood pressure. All of them had a mild (systolic blood pressure > 140 mmhg, diastolic >90 mmhg and proteinuria 300 mg/24 h or + 1 dipstick) or severe preeclampsia (systolic blood pressure > 160 mmhg, diastolic > 100 mmhg and severe proteinüria 2 g/24 h or +2 dipstick). The diagnosis of gestational hypertension was made in women whose blood pressure reached 140/ 90 mmhg or greater for the first time during pregnancy but in whom proteinüria was not developed 7. Women with twin pregnancies, chromosomal abnormalities, intrauterine foetal growth retardation, gestational diabetes, presence of reverse waveform, absence of the end diastolic waveform of umbilical artery were excluded from the study. Those included were followed by periodical nonstress test (NST), amnion fluid volume measurements until delivery. The UA S/D ratio was calculated from three or more successive waveforms obtained from a free floating portion of the umbilical cord during minimal foetal activity and the absence of foetal breathing. All measurements were performed in the semi recumbent positions with the head and chest slightly elevated. For measurement of the MCA, an axial view of the foetal head was YALTI et al : DOPPLER INDICES & FOETAL OUTCOME 45 obtained at the level of cerebral peduncles, then the color Doppler Acuson 128 XP-10 Ultrasonography (Acuson Mountain View, CA) was used to visualize the circle of Willis, and Doppler sample volume was placed within 1 cm of the origin of the MCA that was easily identified as a major branch running anterolateral from the circle of Willis toward to the lateral edge of the orbit. The angle between the ultrasonographic beam and direction of blood flow was always <30 degrees. The Doppler signals were recorded with a 3.5 mhz curved array duplex transducer. The Doppler evaluations were performed by two doctors. Interobserver variation was 7.3 per cent and intraobserver variations were 9.1 and 8.8 per cent. The attending obstetricians had access to the MCA/UA ratio values, MCA/UA<1 was considered abnormal 8. Periodic follow-up was performed using NST, amniotic fluid measurements, and foetal MCA/UA ratio 9. Further management was done depending upon the severity of preeclampsia, hypertension, and condition of the cervix. Women who were near enough to term were managed conservatively until labor commenced spontaneously or until the cervix became favourable for labour induction. Once severe preeclampsia was diagnosed the obstetrical propensity was for prompt delivery. Labour and delivery, and neonatal records were reviewed. Outcome variables studied included pregnancy induced hypertension, MCA/UA ratio, abnormal foetal distress, overall caesarean section rate, birth weight, Apgar scores 10, umbilical cord blood gases analyses, and admission to NICU. Labour and delivery and neonatal records were reviewed immediately following delivery and a segment of cord approximately cm in length was isolated by clamping. Arterial and venous blood samples were obtained in standard heparinized blood sampling syringes after the cord had been doubly clamped. Foetal cord blood po 2 and pco 2, ph values 11, 1 and 5 min Apgar scores 10, rate of sepsis, necrotising enterocolitis, respiratory distress syndrome, meconium aspiration syndrome, hyperbilirubinaemia, hypoxia were recorded. Statistical analysis of data was performed by SPSS-10 computer programme. Mann-Whitney U test, Chi-square and Fisher exact test, Spearman correlation test were used. P < 0.05 was considered significant. The best cut-off levels of MCA and MCA/UA ratios were calculated by ROC (receiver operating curve) analyses. Sensitivity, specificity, positive and negative predictive values of MCA, UA, MCA/UA and 1-specificity for different cut-off levels of MCA and

3 46 INDIAN J MED RES, JULY 2004 MCA/UA ratios in the prediction of low umbilical cord blood ph were calculated. The cut-off value with high sensitivity and low 1-specificity was accepted as the best cut-off value. Umbilical artery blood ph was the gold standard in this test. MCA/UA ratio relative risk was 2.59, 95 per cent confidence interval which did not include 1 and was statistically significant. MCA and UA relative risks were 0.92, 95 per cent confidence interval and 1.35, 95 per cent confidence interval respectively. Kappa statistical analyses were used for inter-and intraobserver variation values. Results The 50 women underwent Doppler sonography in the last three weeks of the third trimester and were stratified into 2 groups based on the MCA/UA ratio. Group A, MCA/UA ratio>1 (n=34); group B MCA/UA ratio (n=16). There was statistically significant increase in perinatal morbidity in cases with cerebro-placental ratio <1 (P<0.05). There were no significant differences in maternal age, gestational age, and parity, systolic and diastolic blood pressure, proteinüria (Table I). There were no differences between the two groups with respect to the foetal cardiotocographic test results, amniotic fluid volum estimation and umbilical artery pulsatility indices. Umbilical artery resistance indices and systolic/diastolic (A/B) ratios were found to be significantly (P<0.01, <0.001 respectively) higher in group B women than group A Doppler measurements (Table II). A significant difference in neonatal weight was found between the two groups (P<0.01). Rate of caesarean delivery was higher in group with MCA/UA ratio<1 (12 cases, 75%) than group with MCA/UA ratio>1 (12 cases, 35.3%) P<0.01 (Table III). Apgar scores at 1 and 5 min were found to be lower in group with MCA/UA ratio <1 than group with MCA/ UA ratio>1. Umbilical cord blood po 2, pco 2 were not different in the two groups; whereas, ph was lower in group with MCA/UA ratio<1 than in group with MCA/ UA ratio>1 (7.2±0.1 versus 7.3±0.1 respectively P<0.001). Sensitivity, specificity, negative and positive predictive values of different cut-off levels of MCA S/D ratio and Table I. Maternal characteristics in the two groups of women (Data are mean±sd) Group A Group B (MCA/UA>1)(MCA/UA 1) (n=34) (n=16) Maternal age (yr) 27.6± ±7.5 Gestational age at recruitment (wk) 37.3± ±1.9 Gravidity 2.8± ±2.9 Systolic blood pressure (mmhg) 158.5± ±24.4 Diastolic blood pressure (mmhg) 101.8± ±11.4 Proteinuria (n, %) 30 (88.2%) 14 (87.5%) MCA/UA, middle cerebral artery/umbilical artery ratio Table II. Results of tests showing foetal well-being in the two groups (Data are mean ±SD) Group A Group B (MCA/UA>1)(MCA/UA 1) (n=34) (n=16) Nonreactive NST n (%) 2 (5.9) 2 (12.5) Decreased AFI n (%) 4 (11.8) 1 (6.3) UA PI 0.9± ±0.2 UA RI 0.6± ±0.1* UA S/D 2.4± ±0.5** P*<0.01; **0.001 compared to Group A NST, Non stress test AFI, amniotic fluid volume UA PI, Umbilical artery pulsatility index UA RI, Umbilical artery resistance index S/D, systolic/diastolic ratio Table III. Delivery routes and foetal findings at delivery in two groups (Data are mean±sd) Group A Group B (MCA/UA>1) (MCA/UA 1) (n=34) (n=16) Foetal weight at birth (g) ± ±587.6* Route of delivery n, (%) Vaginal 22 (64.7) 4 (25)** C/S 12 (35.3) 12 (75) 1 min Apgar 8.1± ±1.5** 5 min Apgar 9.4± ±1.0** UA blood ph 7.3± ±0.1** UA po 2 (mmhg) 25.0± ±6.3 UA pco 2 (mmhg) 44.4± ±7.6 P*<0.01; **<0.001 compared to Group A UA, Umbilical artery C/S, caesarean

4 cerebral index in the prediction of low umbilical cord blood ph were calculated. Best cut-off levels of MCA, MCA/UA ratios were found to be 3 and 1, respectively. According to literature, the best cut-off level of umbilical artery S/D ratio was accepted as All statistical analyses were performed using these cut-off levels. A linear relationship was noted between MCA/UA ratio and umbilical artery blood ph (r=0.355, P<0.05) (Fig. 1), 1 min Apgar scores (r=0.415, P<0.01) (Fig. 2) and 5 min Apgar scores (r=0.365, P<0.01) (Fig. 3) and it was found that most of the adverse outcome group clustered in the women with MCA/UA ratio < 1. Table IV shows the relationship of abnormal MCA/ UA ratio with same outcome variables. Two neonate (5.9%) in group with MCA/UA ratio >1 vs 12 cases (75%) with MCA/UA ratio <1 required neonatal intensive care unit (NICU) (P<0.001). Discussion The use of Doppler ultrasound in high risk pregnancies appears to improve a number of obstetric care outcomes and promising in reducing perinatal deaths 13. Foetuses with abnormal Doppler velocimetry had a significantly higher incidence of oligohydramnios, low birth weight and admission to NICU. Umbilical velocimetry, however is a test of placental function that does not always directly reflect foetal status 5. In our study, sensitivity, positive predictive values of umbilical artery Doppler indices alone were 30 and 50 per cent respectively. Advances in Doppler ultrasonography have improved access to the foetal circulation. There has been a great deal of interest in the foetal intracranial vessels 13. Knowledge of Doppler flow velocimetry of the foetal MCA may assist in perinatal diagnosis and management of complicated pregnancies. A low index of resistance in the middle cerebral artery associated with foetal compromise has been described In our study, sensitivity and positive predictive values of MCA S/D alone were 50 and 46.7 per cent respectively. This is accordance with the literature 11. Because the cerebroplacental ratio incorporates data not only on placental status but also on foetal response, it was felt to be potentially more advantageous in predicting outcome. Doppler data combining both umbilical and cerebral velocimetry provide additional information on foetal consequences of the placental abnormality 18. YALTI et al : DOPPLER INDICES & FOETAL OUTCOME Umbilical artery blood ph r=0.355, P< Fig.1. Scattergraph showing positive correlation between MCA/ UA ratio and umbilical artery blood ph. 1 min. Apgar score MCA/UA ratio r=0.415, P< MCA/UA ratio Fig.2. Scattergraph showing positive correlation between MCA/ UA ratio and 1 min Apgar score. 5 min. Apgar score r=0.365, P< MCA/UA ratio Fig.3. Scattergraph showing positive correlation between MCA/ UA ratio and 5 min Apgar score.

5 48 INDIAN J MED RES, JULY 2004 Table IV. Normal and abnormal MCA/UA ratio in relation to need for neonatal intensive care unit, foetal sepsis, necrotising enterocolitis, respiratory distress syndrome, meconium aspiration syndrome, hyperbilirübinaemia and hypoxia Group A (MCA/UA>1) (n=34) Group B (MCA/UA 1) (n=16) Need for NICU (n, %) 2 (5.9) 12 (75.0)** Sepsis n, (%) 0 0 NEC n, (%) 1 (2.9) 0 (0) RDS n, (%) 0 (0) 3 (18.8)* MAS n, (%) 1 (2.9) 6 (37.5)* Hyperbilirübinaemia n, (%) 2 (5.9) 0 (0) Hypoxia n, (%) 1 (2.9) 9 (56.3)* P*<0.01, **<0.001 compared to Group A NICU, Neonatal intensive care unit NEC, Necrotising enterocolitis RDS, Respiratory distress syndrome MAS, Meconium aspiration syndrome In the present study, sensitivity and positive predictive value of MCA/UA ratio alone were 55 and 68.7 per cent respectively. The cerebroplacental ratio, defined as the cerebral index divided by the umbilical resistance index, showed a close correlation with foetal po 2 in pregnant women during umbilical cord clamping or aortic compression 19. In foetuses with abnormal MCA/UA, Doppler ratio are strongly correlated with worse foetal prognosis. In normal pregnancies the diastolic component in the cerebral arteries is lower than in the umbilical arteries at any gestational age. Therefore, the cerebro-vascular resistance remains higher than the placental resistance and the cerebro-placental ratio is greater than 1. The index becomes less than 1 if the flow distribution is in favour of the brain in pathological pregnancies. We observed reduction in placental perfusion and an increase in flow towards the brain. This phenomenon, called the brain sparing effect, is supposed to compensate for foetal hypoxia and is associated most of the time with foetal growth retardation with low umbilical artery ph. In the first approach it appears difficult to use the cerebral index to quantify hypoxia. One can expect follow up the evaluation of hypoxia through the cerebrovascular changes. The cerebrovascular index decreases progressively, as in the normal foetuses so the hypoxia to be compensated by the brain hyperperfusion 20. The cerebral index which was much lower than normal limit increases and enters the normal range. In this case the capability of the brain vessels to vasodilate has been overloaded. Hypoxia gets compensated and foetus becomes acidemic. In the normal foetus it is apparent that both ph and PO 2 decrease significantly with advancing age, while PCO 2 and base excess increase. The progressive fall in the foetal PO 2 with advancing gestation is probably due to increased O 2 consumption by the placenta 17. Seikuza et al 11 found positive correlation between the umbilical artery, and MCA RI and umbilical cord blood ph, whereas there was negative correlation between cerebral index and umbilical cord blood pco But the best correlation was between cerebral index and cord blood ph and cord blood gases levels. Like Seikuza et al 11, Akalin et al 21 also reported same findings. Unlike these studies, we found positive correlation between MCA/UA ratio and umbilical cord blood ph. When the cerebral index ratio was less than 1, ph levels were found to be below normal limits for the third trimester (7.41±0.02) and there was a negative correlation between cerebral index ratios and blood ph. We observed that the CO 2 and O 2 levels were below the normal limits in both the groups. Especially in cases with cerebral index <1, blood gases were within acute (less than h) respiratory acidosis levels. None of the women had a mortal foetal prognosis. According to the present cord blood gas findings, there was no compensatory decrease in CO 2 levels indicating metabolic acidosis. Foetuses born to group B women stayed longer in the neonatal intensive care unit. A higher percentage of mothers with an abnormal MCA/UA Doppler ratio underwent cesarean section. Newborn hypoxia, low Apgar score, complicated delivery, and meconium aspiration syndrome were seen more in group B foetuses. Ashmead et al 22 showed five foetuses with absence of end diastolic flow had normal blood gases, yet an increased foetal morbidity. The cerebral indices were not taken into account in this study 22. Though this study 22 had small number of cases, similar to our findings, they found no correlation between Doppler events and cord blood gas levels. Brar et al 23 recognized that Doppler studies of the internal carotid artery or a ratio of cerebral to umbilical resistance could be used to identify pregnancies with a

6 YALTI et al : DOPPLER INDICES & FOETAL OUTCOME 49 compromised post date foetus. The foetuses in our study with adverse outcome had a lower middle cerebral artery S/D ratio, supporting the finding of Brar et al 23. In our study we excluded IUGR pregnancies. This result may be due to severity or duration of the circulatory impairment of the placenta is not enough to cause birth weight differences and on the basis of previous published studies 5,24. Doppler velocimetry studies of placental and foetal circulation can provide important information regarding foetal well-being, yielding an opportunity to improve foetal outcome 25. Although the sample size of our study was small, our results suggested that the MCA/UA Doppler ratio of less than 1 was a good predictive tool for neonatal outcome in preeclamptic and hypertensive pregnant women and could be used to identify foetuses at risk of morbidity. References 1. Kurjak A, Kupesic S, Zudenigo D. Doppler ultrasound in all three trimesters of pregnancy. Curr Opin Obstet Gynecol 1994; 6 : Kassanos D, Siristatidis C, Vitoratos N, Salamalekis E, Creatsas G. The clinical significance of Doppler findings in fetal middle cerebral artery during labor. J Obstet Gynecol Reprod Biol 2003; 109 : Sterne G, Shields LE, Dubinsky TJ. Abnormal fetal cerebral and umbilical Doppler measurements in fetuses with intrauterine growth restriction predicts the severity of perinatal morbidity. J Clin Ultrasound 2001; 29 : Arduini D, Rizzo G, Romanini C. Changes of pulsatility index from fetal vessels preceding the onset of late decelerations in growth retarded fetuses. Obstet Gynecol 1992; 79 : Arias F. Accuracy of the middle-cerebral-to-umbilical-artery resistance index ratio in the prediction of neonatal outcome in patients at high risk for fetal and neonatal complications. Am J Obstet Gynecol 1994; 171 : Makhseed M, Jirous J, Ahmed MA, Viswanathan DL. Middle cerebral artery to umbilical artery resistance index ratio in the prediction of neonatal outcome. Int J Gynaecol Obstet 2000; 71 : Cunnigham FG, Gant NF, Leveno KJ, Gilstrap LC, Hauth JC, Wenstrom FD. Hypertensive disorders in pregnancy: In: Seils A, Noujaim SR, Devis K, editors. Williams obstetrics, 21st ed. USA: The McGraw-Hill; 2001 p Williams KP, Wilson S. Maternal ceresbral blood flow changes associated with eclampsia. Am J Perinatol 1995; 12 : Ott WJ, Mora G, Arias F, Sunderji S, Sheldon G. Comparison of the modified biophysical profile to a new biophysical profile incorporating the middle cerebral artery to umbilical artery velocity flow systolic/diastolic ratio. Am J Obstet Gynecol 1998; 178 : Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg 1953; 32 : Sekizuka N, Murakoshi T, Yoshizawa H, Tanaka K, Hanaoka J, Takeuchi Y, et al. The relationship between flow velocity waveforms of umbilical and fetal middle cerebral arteries and cord blood gas values. Nippon Sanka Fujinka Gakkai Zasshi 1993; 45 : Ducey J, Schulman H, Farmakides G, Rochelson B, Bracero L, Fleischer A, et al. A classification of hypertension in pregnancy based on Doppler velocimetry. Am J Obstet Gynecol 1987; 157 : Neilson JP, Alfirevic Z. Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev 2000 : CD Madazli R, Uludag S, Ocak V. Doppler assessment of umbilical artery, thoracic aorta and middle cerebral artery in the management of pregnancies with growth restriction. Acta Obstet Gynecol Scand 2001; 80 : Severi FM, Bocchi C, Visentin A, Falco P, Cobellis L, Florio P, et al. Uterine and fetal cerebral Doppler predict the outcome of third trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2002; 19 : Dubiel M, Gudmundsson S, Gunnarsson G, Marsal K. Middle cerebral artery velocimetry as a predictor of hypoxemia in fetuses with increased resistance to blood flow in the umbilical artery. Early Hum Dev 1997; 47 : Seyam YS, Al-Mahmeid MS, Al-Tamimi HK. Umbilical artery Doppler flow velocimetry in intrauterine growth restriction and its relation to perinatal outcome. Int J Gynaecol Obstet 2002; 77 : Bahado-Singh RO, Kovanci E, Jeffres A, Oz U, Deren O, Copel J, et al. The Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet Gynecol 1999; 180 : Arbeille PH, Body G, Saliba E, Tranquart F, Berson M, Roncin A, et al. Fetal cerebral circulation assessment by Doppler ultrasound in normal and pathological pregnancies. Eur J Obstet Gynecol Reprod Biol 1988; 29 : Rizzo G, Arduini D, Luciano R, Rizzo C, Tortorolo G, Romanini C, et al. Prenatal cerebral Doppler ultrasonography and neonatal neurologic outcome. J Ultrasound Med 1989; 8 :

7 50 INDIAN J MED RES, JULY Akalin-Sel T, Nicolaides KH, Peacock J, Campbell S. Doppler dynamics and their complex interrelation with fetal oxygen pressure, carbon dioxide pressure, and ph in growth-retarded fetuses. Obstet Gynecol 1994; 84 : Ashmead GG, Lazebnik N, Ashmead JW, Stepanchak W, Mann LI. Normal blood gases in fetuses with absence of end diastolic umbilical artery velocity. Am J Perinatol 1993; 10 : Brar HS, Horenstein J, Medearis AL, Platt LD, Phelan JP, Paul RH. Cerebral, umbilical and uterine resistance using Doppler velocimetry in postterm pregnancy. J Ultrasound Med 1989; 8 : Ott WJ. Value of fetal umbilical artery and carotid Doppler flow studies in the evaluation of suspected intrauterine growth retardation. J Matern Fetal Invest 1991; 1 : Bhatt AB, Tank PD, Barmade KB, Damania KR. Abnormal Doppler flow velocimetry in the growth restricted foetus as a predictor for necrotising enterocolitis. J Postgrad Med 2002; 48 : Reprint requests : Dr Serap Yalti, Kocatürk Sitesi, A. Blok, Kat: 3, D:6, Acibadem, Kadikoy, Istanbul, Turkey serapyalti@yahoo.com