Wesam Kurdi, FRCOG Head, Section of Maternal Fetal Medicine Department of Obstetrics & Gynecology

1. Doppler Ultrasound in Daily Practice Wesam Kurdi, FRCOG Head, Section of Maternal Fetal Medicine Department of Obstetrics & Gynecology King Faisal Specialist Hospital & Research Center Riyadh,Saudi Arabia

2. Uses of Doppler Ultrasound in Obstetrics Doppler in IUGR Doppler in fetal anemia Doppler in Multi-fetal pregnancy evaluation Doppler in the assessment of the fetal heart Doppler in fetal structural abnormalities Doppler in placental and cord abnormalities Doppler in early pregnancy evaluation Doppler in screening for chromosomal abnormalities

3. Practical PointsFactors affecting the waveform • Fetal breathing

4. Practical PointsFactors affecting the waveform • The indices are higher at the fetal than at the placental end of the cord, usually free loop is used • Gestational age: end-diastolic velocity increases with advancing gestation • Fetal heart rate: can effect Doppler indices, but within the normal limits of the fetal heart rate (120 to 160 bpm), the changes in the Doppler indices are not significant. • Fetal behavioral states: no effect

5. Practical PointsFactors affecting the waveform • Angle of insonation: the higher the angle, the smaller the waveform, preferable to keep the angle of insonation as close to zero as possible Remember: cos 0= 1 cos 30= 0.87 cos 60= 0.5 cos 90= 0 2f v cos c fd =

6. Effects of the angle Good angle Bad angle

7. UTERINE ARTERY DOPPLER

8. UTERINE ARTERY DOPPLER

9. UTERINE ARTERY DOPPLER Notching by Gestation Highest risk Persistant bilateral notching after 24 weeks Less risk Unilateral notches Normalization by 24 weeks

10. UTERINE ARTERY DOPPLER Persistent notching at 24 weeks

11. Uterine Artery Doppler Screening studies for the prediction of pre-eclampsia 7-33% low Very good 24-77% Very good  CI, confidence interval; LR, likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Prev, prevalence; Sens, sensitivity; Spec, specificity; SPR, screen positive rate.

12. Uterine Artery Doppler Screening studies for the prediction of fetal growth restriction below the 10th centile higher Lower Borderline IUGR more heterogeneous CI, confidence interval; LR, likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Prev, prevalence; Sens, sensitivity; Spec, specificity; SPR, screen positive rate.

13. Uterine Artery Doppler Screening studies for the prediction of fetal growth restriction below the 5th and 3rd centile 12-19% Very good CI, confidence interval; FGR, fetal growth restriction; LR, likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Prev, prevalence;

14. Doppler Ultrasound in IUGR Why is it important to diagnose IUGR? • IUGR are at increased risk of complications: • Fetal hypoxia and acidemia • 3-10 fold  risk of perinatal mortality and morbidity • Long-term intellectual and neurological impairment. Perinatal/ Post-natal Problems Asphyxia, Temperature instability, Hypoglycemia, Fetal Distress, Acidosis, Meconium aspiration, Polycythemia, Impaired growth and development, Adult disease: cardiac, diabetes

15. Umbilical Artery DopplerScreening in High Risk Pregnancy • Reduces hospital admissions (OR 0.56, CI= 0.43- 0.72) • Reduces IOL (OR 0.83, CI=0.74-0.93) • Trend to lower Perinatal Mortality Rate (OR 0.71, CI= 0.5-1.01) • No difference for fetal distress (OR 0.81, CI= 0.59-1.13), or CS rate ( OR 0.94, CI= 0.82-1.06) Cochrane Database 2000

16. Fetal and umbilical Doppler ultrasound in high-risk pregnancies Eighteen completed studies involving just over 10,000 women were included. RR 95%CI Perinatal deaths 0.71 0.52 to 0.98 IOL 0.89 0.80 to 0.99 Caesarean sections 0.90 0.84 to 0.97 Operative vaginal births 0.95 0.80 to 1.14 Apgar  7 at 5min 0.92 0.69 to 1.24 Numbers needed to treat 203 AUTHORS' CONCLUSIONS: Current evidence suggests that the use of Doppler ultrasound in high-risk pregnancies reduced the risk of perinatal deaths and resulted in less obstetric interventions. The quality of the current evidence was not of high quality, therefore, the results should be interpreted with some caution. Studies of high quality with follow-up studies on neurological development are needed. Alfirevic Z, Cochrane Database Syst Rev. 2010

17. IUGR with normal UA Doppler Neonatal and maternal outcomes Twice-weekly Fortnightly monitoring (n=85) monitoring (n=82) Neonatal outcome Gestational age at delivery (d, mean  SD)264  13 268  12* Umbilical artery resistance index at delivery (mean  SD) 0.63  0.08 0.61  0.06 Abnormal umbilical artery resistance index at delivery (No.) 5 (6%) 1 (1%) Female sex (No.) 43 (51%) 46 (56%) Birth weight (g, mean  SD) 2534  454 2587  412 Birth weight <10th percentile (No.) 47 (55%) 57 (69%) Ponderal index (mean  SD) 2.42  0.29 2.40  0.28 Ponderal index <10th percentile (No.) 29 (34%) 39 (48%) Admission to neonatal nursery (No.) 26 (31%) 28 (34%) Neonatal hospital stay (d, median and range) 5 (0-66) 4 (1-27) Acidosis at birth (No.) 4 (5%) 3 (4%) Hypoglycemia (No.) 16 (19%) 18 (22%) Maternal outcome (No.) Spontaneous onset of labor8 (9%) 21 (26%†) Induction of labor70 (82%) 54 (66%†) Cesarean delivery 13 (15%) 11 (13%) Cesarean delivery for fetal distress 7 (8%) 7 (9%) Preeclampsia 4 (5%) 1 (1%) Gestational hypertension 20 (24%) 13 (16%) *p<0.05 †p<0.02 McCowan et al 2000 167 IUGR fetuses

18. Clinical Management of IUGR How reassuring is a normal test result? Stillbirth rate within one week of a normal test NST 1.9/1000 (5861 patients) CST 0.3/1000 (12656 patients) BPP 0.8/1000 (44828 patients) Modified BPP (NST + AFI) 0.8/1000 (54617 patients) UA Doppler 0/1000 (214 patients)

19. Umbilical Artery Dopplerand Poor Fetal Outcome Sensitivity Specificity PPV NPV Abnormal outcome 79% 93% 83% 91% SGA 75% 77% 32% 95% FD, pH, Apgar, NICU 86% 68% 96% 69% FD, pH, Apgar, NICU, Mec 82% 92% 81% 74% Abnormal NST 93% 78% 8.4% 99.8 Fetal distress 70% 89% 31% 97.5% CS for FD 9% 88.8% 21.6% 99.7% • 1410 tests done • Increased RI occur prior to changes on NST • Simple, efficient • Mean time 6 min vs 27 min for NST

20. Umbilical Artery Doppler +ve EDF -ve EDF Reverse EDF P IUFD 3% 14% 24% <0.001 Cesarean Section 56% 96% 96% <0.001 NICU 60% 96% 98% <0.001 Severe RDS 3% 17% 41% <0.001 Severe IVH 1% 9% 35% <0.01 NEC 3% 5% 9% 0.2 459 High Risk Pregnancies, Karsdorp et al, 1994 1126 cases of AEDV: Stillbirth rate: 170/1000 ENMR 280/1000 cPMR 340/1000 Maulik, 2005

21. Can Umbilical Artery Doppler Predict the Sick IUGR? Parameter AEDF REDF Gest age 34 wks 29 wks C/S 77.6% 95.6% Fetal distress 31.3% 60.4% Bt Wt < 3rd 13.4% 57.8% Acidemia 4.5% 20.8% 115 fetuses with AC < 5th Doppler performed 24 hours before delivery • Abnormal umbilical artery Doppler is more predictive of neonatal outcome than EFW. • If EDF present and PI > 2SD from mean, 90% will deliver vaginally.

22. A randomised trial of timed delivery for the compromised preterm fetus: short term outcomesGRIT Study Group, BJOG. 2003;110(1):27. • Randomized controlled trial, 69 hospitals in 13 European countries. • Pregnant women with fetal compromise between 24 and 36 weeks, an umbilical artery Doppler waveform recorded and clinical uncertainty whether immediate delivery was indicated. • METHODS: The interventions were 'immediate delivery' or 'delay until the obstetrician is no longer uncertain'. The data monitoring and analysis were Bayesian. • MAIN OUTCOME MEASURES: 'Survival to hospital discharge' • 548 women (588 babies) recruited, outcomes were available on 547 mothers (587 babies). Immediate gp Delayed gp Median time-to-delivery intervals were 0.9 days 4.9 days Death prior to discharge 10% 9% OR: 1.1, 95% CI 0.61-1.8 cesarean section 91% 79% OR 2.7; 95% CI 1.6-4.5

23. MIDDLE CERABRAL ARTERY DOPPLER Easy to study Main branch of the circle of Willis Carries 80% of blood flow to the ipsilateral cerebral hemisphere Carries 3-7% of cardiac output throughout gestation

24. MIDDLE CERABRAL ARTERY DOPPLER Relation to neurodevelopment • Decrease MCA PI is an adaptive process protecting the fetus against severe brain damage. • 3 years follow-up failed to demonstrate neurodevelopmental abnormalities with decreased MCA PI. Scherjon 1998 • Drop in MCA PI may be protective against IVH but prematurity is the greatest predictor. Mari 1996

25. Performance of single Doppler measurement for major adverse perinatal outcome at <32 weeks. Sensitivity Specificity PPV NPV UA 59.1 69.7 32.5 87.3 MCA 95.9 47.2 30.9 97.9 UA - better for screening MCA - reassurance if normal

26. Venous Doppler The fetal venous system Doppler waveformsevaluates the fetal heart compensation to severe growth restriction. • The commonly studied vessels include: • Umbilical vein • Ductus venosus

27. Relation between UA and UV • AEDF in UA no pulsation: 19% mortality pulsation: 63% mortality Intra-abdominal part is more sensitive than the free loop, pulsation in the free loop is a very bad sign.

28. Progression of fetal growth restriction

29. Sequence of Doppler Changes in IUGR Brain sparing Asymmetrical IUGR Oligohydramnios 2 weeks prior to CTG changes Possibly with CTG changes

30. Arterial and Venous Doppler and Perinatal Death Sensitivity Specificity PPV NPV UA 100 50 42 100 MCA 60 29 23 67 UV 80 50 36 88 DV 80 93 80 93 Ozcan et al 91 1998

31. Duration of persistent abnormal ductus venosus flow and its impact on perinatal outcome in fetal growth restriction. • 171 patients with 1069 examinations. Duration of an absent/reversed a-wave in the DV (DV-RAV) Stillbirth 6 days Intact survivors 0 days P = 0.006 Major morbidity 0 days P = 0.001 Duration of brain sparing Stillbirth 19 days Intact survivors 9 days P = 0.02 Gestational age at delivery was a significant codeterminant of outcome for all arterial Doppler abnormalities when the DV a-wave was positive. When DV-RAV is found, this was the only contributor to stillbirth DV-RAV for>7 days predicted stillbirth 100% sensitivity, 80% specificity, LR = 5.0, P<0.0001 Neither neonatal death nor neonatal morbidity was predicted by the days of persistent DV-RAV. • CONCLUSIONS: The duration of absent or reversed flow during atrial systole in the DV is a strong predictor of stillbirth that is independent of gestational age. While prematurity remains the strongest predictor of neonatal risks it is unlikely that pregnancy can be prolonged by more than 1 week in this setting. Turan OM, et al, Ultrasound Obstet Gynecol. 2011;38(3):295

32. Clinical Follow-up Normal umbilical and MCA Doppler NST and venous Doppler not indicated Abnormal umbilical and MCA Doppler > 34 weeks < 30 weeks delivery Venous Doppler + NST 30-34 weeks Normal Abnormal Individualize according to findings, history and neonatal facilities Steroids, close observation Consider delivery

33. Timing of Delivery The risk of death or cerebral palsy reduces as each week goes by, but if delivery is delayed until there is fetal circulatory collapse (very abnormal venous blood flows), the risk of death is also increased. Harnington, Ultra OB Gyn 2000;16:399-401

34. TAKE HOME MESSAGES • Umbilical artery Doppler can help to guide decision making and the need for further fetal monitoring. • Absent/ reversed EDF when linked with abnormal CTG increases the risk of poor cognitive outcome in childhood. • Arterial redistribution predicts hypoxemia. • Venous Doppler abnormalities predicts heart failure. • Venous system is the fine tuning area for planning the delivery. • Appearance of a reverse a wave in the DV or pulsation in the umbilical vein is a strong indication for delivery. • Gestational age has the greatest influence on fetal wellbeing

35. Practical Points • Overall survival of IUGR at < 26 weeks is <50%, intact survival is <50%. • Gestational age is more important than Doppler at < 26 weeks. • Intact survival are not much related to birth weight. • Outcome is better if less obvious CTG/ Doppler abnormalities are present. • Waiting reduces the risk of lung complications, but not NEC or IVH • Long term outcome: higher rates of disability in the earlier delivery group- mostly in < 30 weeks fetuses. • Once severe redistribution occurs, further follow-up with arterial Doppler is not very helpful for timing of delivery. • Between 26 and 29 weeks: each day in utero has been estimated to improve survival by 1-2% • Arterial changes have been reported to last for up to 6 weeks, depending on gestational age, presence of venous pulsation, and maternal disease.

37. Fetal Anemia • Red cell immunization • Parvovirus infection • Massive fetomaternal hemorrhage • Hematologic disorders: Alpha-thalassemia, G6PD • Large placental chorioangioma • Twin-twin transfusion syndromes • Intracranial hemorrhage

38. What are the Effects of Severe Fetal Anemia

39. Prediction of Fetal Anemia A variety of ultrasonographic parameters have been used to detect fetuses at risk of anemia: • Placental thickness: not been considered to be very reliable and reproducible in clinical practice. • Hepatic length greater than or equal to the 95th percentile: the liver is difficult to visualize and measure adequately, particularly when the fetus is in an unfavorable position (back up or right side up). • Splenic enlargement: a splenic perimeter greater than 2 SD has predicted severe fetal anemia with a positive predictive value of 94%. It was found to be an excellent predictor of severe fetal anemia in cases before the first transfusion, with sensitivity and specificity of 100 and 94.7%, respectively, but the predictive value was not as good in patients with prior transfusion or with mild anemia. • Main splenic artery PSV: there was no risk of severe anemia with PSV below the median for gestational age, but the prediction is not good for mild anemia.

40. Prediction of Fetal Anemia A prospective cohort study compared Doppler and ultrasound parameters to predict fetal anemia in alloimmunized pregnancies. Sensitivity MCA-PSV 100% Intrahepatic umbilical venous maximal velocity 83% Liver length 66% Spleen perimeter 33% MCA-PSV is the best available noninvasive test in the prediction of fetuses at risk of anemia

41. Prediction of Fetal Anemia • Multicentric study the sensitivity of MCA-PSV for predictions of moderate and severe anemia prior to the first cordocentesis: Sensitivity 100% False positive rates 12% for 1.50 MoM • Multicenter trial for timing a cordocentesis: MCA-PSV is an accurate method of monitoring pregnancies Number of false positives increased following 35 weeks' gestation • Prospective study compared MCA-PSV with Delta OD 450: Both procedures are useful in the prediction of fetal anemia But Doppler ultrasound is less expensive and noninvasive than amniocentesis

42. Doppler and Fetal Anemia Normal fetuses Anemic fetuses MCA MoM > 1.5 MoM MCA peak velocity Sensitivity 100% False +ve 12% Positive predictive rate 65% Negative predictive rate 100%

43. Management of Rh(-) Immunized Patients +ve antibody screen Paternal genotype Negative Heterozygous Homozygous No further testing (paternity!) Consider fetal blood typing Follow protocol The RhD gene was cloned, PCR for fetal RhD status can be performed on amniocytes or CVS specimen, inaccuracy 0.3-2% Fetal DNA in maternal circulation: 100% accuracy

44. Modern management of red-cell alloimmunization • MCA-PSV should be performed in fetuses at risk of fetal anemia on a weekly basis for three consecutive weeks. • Cordocentesis is indicated when the MCA-PSV value is over 1.5 MoM. • If the MCA-PSV remains below 1.5 MoM a regression line has to be obtained from the following three values. Repeat weekly Repeat Q1-2 wks Repeat Q2-4 wks

45. Can the Peak Systolic MCA Doppler Assessment Be Used to Time Serial IUTs? The decreasing sensitivity MCA-PSV after several IUTs has several explanations: • By the third IUT, most of the circulating red cells in the fetal circulation are donor cells that contain adult hemoglobin. • Correction of the fetal anemia through IUT raises the fetal hematocrit level, which also substantially increases whole blood viscosity. Both of these will slow the speed at which blood moves through the fetal circulation. The average drop in Hg following donor transfusion is 0.4gm/ day

46. Validity of MCA PSV in determining severe anemia in previously transfused fetuses Wesam Kurdi Maisoon AlMugbel Fatima AlAbri Elham AlMardawi Maha Tulbah Khalid Awartani King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia

47. Objectives To assess if the correlation between the MCA PSV and fetal hemoglobin is maintained in fetuses who received multiple IUT’s Patients and Methods • Retrospective analysis on all pregnant women who received IUT’s at King Faisal Specialist Hospital (January 2006 to December 2010). • Doppler measurement of MCA PSV performed before cordocentesis. • MCA PSV and fetal Hb expressed as multiples of the median (MoM). • MCA PSV ≥ 1.5 MOM used as a predicator for severe anemia (Hb ≤ 0.55 MoM) MCA PSV in previously transfused fetuses

48. MCA PSV in previously transfused fetuses Results • 28 pregnancies, non-hydropic fetuses; GA at 1st visit 24 + 4.6 wks • Parity: 5.2 (range 1-11); Living children: 4.1 (range 1-8) • 64% had IUTs in previous pregnancy n GA Hb g/L Hb ≤0.55 FPR DR Before 1st 28 22.6 57 (14-95) 57% 43% 100% Before 2nd 25 26.9 59 (10-114) 48% 54% 92% Before 3rd 21 29.2 78 (50-127) 33% 61% 78% Before 4th-6th 30 31.9 80 (45-110) 33% 76% 81% Any anemia, PSV cut-off 1.5 MoM 0% 81% Any anemia, PSV cut-off 1.4 MoM 0% 91% • GA at delivery: 36.3 wks; Delivery at >35 wks: 66% • Survival rate: 83%; Postnatal mean Hb: 124g/L

49. MCA PSV in previously transfused fetuses Conclusions • In the prediction of severe fetal anemia by MCA PSV: The FPR increases and DR decreases with increasing number of IUT’s • Severity of anemia is reduced with repeated IUT’s • Reducing the MCA PSV to 1.4 MoM after the 3rd IUT improves the DR to 91% • What should our end point be for mature fetuses: any anemia or severe anemia?

50. Kell alloimmunization • The mechanism of anemia in Kell alloimmunization is in direct suppression of erythropoiesis in conjunction with sequestration of sensitized red cells. • Evaluation of at-risk fetuses with MCA PSV has a sensitivity and specificity of 89% for the detection of fetal anemia, similar to the detection of fetal anemia in RhD alloimmunization.