Doppler in Obstetrics by Nicolaides, Rizzo, Hecker & Ximenes
The 11-14 weeks scan by Nicolaides, Sebire, Snijiders & Ximenes
The 18-23 weeks scan by Pilu, Nicolaides, Ximenes & Jeanty
 
PATHOPHYSIOLOGY
In red cell isoimmunized pregnancies, maternal hemolytic antibodies cross the placenta and attach themselves onto fetal red cells, which are then destroyed in the fetal reticulo-endothelial system1. In mild to moderate disease there is a compensatory increase in intramedullary erythropoiesis, and in severe disease there is recruitment of extramedullary erythropoietic sites, such as liver and spleen 2,3.

Fetal blood pO2, pCO2 and pH usually remain within the normal range except in extreme anemia, when hypoxia and acidosis occur 4,5. The fetal blood oxygen content decreases in proportion to the degree of anemia. The fetal 2,3-diphosphoglycerate (2,3-DPG) concentration is increased and the consequent decrease in hemoglobin–oxygen affinity presumably improves delivery of oxygen to the tissues 6. In moderate anemia, the umbilical arterial plasma lactate concentration is increased but this is cleared by a single passage of fetal blood through the placenta and normal umbilical venous levels are maintained 7. In severe anemia, when the oxygen content is less than 2 mmol/l, the placental capacity for lactate clearance is exceeded and the umbilical venous concentration increases exponentially. These data suggest that, in the fetus, systemic metabolic acidosis can be prevented, unless the oxygen content decreases below the critical level of 2 mmol/l 7. When the fetal hemoglobin concentration deficit exceeds 6 g/dl, hydrops fetalis develops 1. This may be the result of extensive infiltration of the liver by erythropoietic tissue, leading to portal hypertension, due to parenchymal compression of portal vessels, and hypoproteinemia, due to impaired protein synthesis 8. Furthermore, at this hemoglobin concentration deficit, the oxygen content decreases below the critical level of 2 mmol/l.
DIAGNOSIS AND TREATMENT OF FETAL ANEMIA

The severity of fetal hemolysis can be predicted from:

(1) The history of previously affected pregnancies;

(2) The level of maternal hemolytic antibodies;

(3) Changes in the flow velocity waveforms obtained by Doppler studies of the fetal circulation;

(4) The altered morphometry of fetus and placenta; and

(5) The presence of pathological fetal heart rate patterns4.

However, there is a wide scatter of values around the regression lines describing the associations between the degree of fetal anemia and the data obtained from these indirect methods of assessment. The only accurate method for determining the severity of the disease is blood sampling by cordocentesis and measurement of the fetal hemoglobin concentration. Cordocentesis should be performed for all patients with a history of severe disease and those with a hemolytic antibody level of more than 15 IU/ml or a titer of 1 in 128 or more9–12. At cordocentesis, a fetal blood sample is first obtained and the hemoglobin concentration is determined. If this is below the normal range, the tip of the needle is kept in the lumen of the umbilical cord vessel and fresh, packed, rhesus-negative blood compatible with that of the mother is infused manually into the fetal circulation through a 10-ml syringe or a transfusion set. At the end of the transfusion, a further fetal blood sample is aspirated to determine the final hemoglobin concentration13,14. Subsequent transfusions are given at 1–3-weekly intervals until 34–36 weeks, and their timing is based on the findings of non-invasive tests, such as Doppler studies, and the knowledge that, following a fetal blood transfusion, the mean rate of decrease in fetal hemoglobin is approximately 0.3 g/dl per day14.

 DOPPLER STUDIES
 
Uterine artery
In a longitudinal study of 12 fetuses, Copel et al. included the uterine artery pulsatility index (PI), together with the descending thoracic aortic peak velocity, in a multiple regression model to predict whether the fetal hematocrit was below or above 25% before the second fetal blood transfusion 15. The authors suggested that the significant contribution of uterine artery PI to the model could be explained by the effect of resolving placental edema after the correction of fetal anemia by the second transfusion. However, this is unlikely because there was no difference in uterine PI between

hydropic and non-hydropic fetuses. In a series of 95 red cell isoimmunized pregnancies, impedance in the uterine artery was within the normal range and there was no significant association between PI and the degree of fetal anemia. Therefore, it is unlikely that fetal anemia alters the uteroplacental circulation.
Umbilical artery
Rightmire et al. found a significant inverse correlation between impedance to flow in the umbilical artery and fetal hematocrit 17 . It was suggested that increased impedance to flow in the fetoplacental microcirculation may be due to hypoxemia-mediated capillary endothelial cell damage, or clogging of the placental capillaries by the large fetal erythroblasts. In contrast, Warren et al . reported that impedance in the umbilical artery was not abnormal in red cell isoimmunized pregnancies with high amniotic fluid bilirubin concentration 18. Similarly, in a study of 95 affected pregnancies, umbilical artery PI, measured immediately before cordocentesis, was not increased and was not associated with fetal anemia 16.
Impedance to flow in fetal vessels
Vyas et al. measured the PI in the middle cerebral artery of 24 non-hydropic fetuses from red cell isoimmunized pregnancies; there were no significant associations between PI and either the degree of fetal anemia or the degree of deficit in oxygen content measured in samples obtained by cordocentesis 12. Furthermore, in a study of 95 fetuses undergoing cordocentesis for rhesus disease, the PI in both the middle cerebral artery and descending thoracic aorta was not significantly different from normal controls and there was no significant association between PI and fetal anemia 16. These findings indicate that impedance to flow is not affected by anemic hypoxia and by the alterations of blood constituents, such as hypoproteinemia, or red cell morphology, such as erythroblastemia, that accompany severe anemia 2,3.
Fetal cardiac Doppler studies
Meijboom et al. measured maximal and mean temporal velocity and early passive to late active ventricular filling phase (E/A) ratio on the atrioventricular orifices in 12 fetuses immediately before fetal blood transfusion 19. There was a non-significant increase in both maximal and mean temporal velocities. Furthermore, there was a significant reversal in the E/A ratio in the flow waveforms from the tricuspid valve. In normal fetuses, these two peaks present an ‘M’ shape, whereas in anemic fetuses the E peak is dominant, suggesting that, in fetal anemia, there is an increased pre-load in the right atrium. Copel et al. found that anemic fetuses before any intrauterine transfusion had significantly higher stroke volumes and ventricular outputs than normal controls. The increase was shared proportionately by both ventricles 20. However, there was no significant relationship between fetal hematocrit and cardiac output. Nevertheless, extremely compromised fetuses demonstrated diminished cardiac function as a terminal finding. In contrast, Barss et al. reported a case of hydrops fetalis where the cardiac output measured before an intravascular transfusion was close to the normal mean for gestation 21.

Rizzo et al. measured right and left cardiac outputs (by multiplying the tricuspid or mitral mean temporal velocities, valvular area and heart rate) in 12 anemic fetuses before blood transfusion by cordocentesis 22. Both left and right cardiac outputs were significantly higher for gestation than in 187 normal controls. Furthermore, the E/A ratios of both atrioventricular valves were higher than normal (Figure 1). Lam et al . examined 20 anemic (due to homozygous a-thalassemia-1) fetuses at 12–13 weeks of gestation and reported increased peak velocities at the pulmonary valve and ascending aorta and an increased inner diameter of the pulmonary valve 23. The total cardiac output was increased by one-third and this was mainly due to an increase of the cardiac output on the right side. The findings of increased fetal cardiac output in anemia are in agreement with the results of animal studies and confirm the prediction, from a mathematical model, that, in fetal anemia, the cardiac output is increased to maintain an adequate oxygen delivery to the tissues 24. Possible mechanisms include, first, decreased blood viscosity leading to increased venous return and cardiac preload and, second, peripheral vasodilatation as a result of a fall in blood oxygen content and therefore reduced cardiac afterload.
Figure 1 - Flow velocity waveforms across the tricuspid valve in an anemic fetus at 28 weeks of gestation. The E/A ratio is increased (0.97 compared to the expected mean for gestation of 0.75).
The high E/A is suggestive of increased cardiac preload. Since right-to-left cardiac output ratio is normal, there is no evidence of redistribution in cardiac output similar to that described in hypoxemic growth-restricted fetuses. These findings suggest that, in fetal anemia, the changes in fetal cardiac output are mainly due to low blood viscosity. An alternative explanation is that the symmetrical increase in cardiac output is secondary to an increase in catecholamine concentrations in fetal blood induced by anemia 25.
Blood velocity in fetal arteries

Rightmire et al . examined 21 fetuses from red cell isoimmunized pregnancies before fetal blood sampling and reported a significant inverse association between aortic mean blood velocity and fetal hemoglobin concentration 17. Similarly, from the examination of 68 previously untransfused fetuses at 17–37 weeks of gestation, Nicolaides et al. reported a significant association between aortic mean velocity, measured immediately before cordocentesis, and the degree of fetal anemia 11. However, separate analysis of non-hydropic and hydropic fetuses demonstrated that in the former group there was a significant positive correlation between increased velocity and fetal anemia, whilst in the latter group there was a significant negative correlation between these two parameters.

In an extended series of 95 previously untransfused fetuses undergoing cordocentesis for rhesus disease, there was a significant increase in aortic velocity with the degree of fetal anemia 16 . Although, in some hydropic fetuses, aortic velocity was decreased, in the majority of cases the velocity was increased. In an additional series of 212 fetuses that had a transfusion 2–3 weeks previously, the relation between aortic velocity and anemia was weaker.

Copel et al
. measured the peak velocity in 16 fetuses immediately before cordocentesis and derived a series of formulae for the prediction of whether the fetal hematocrit was above or below 25% 15 . The best prediction was achieved for the untransfused fetuses. For subsequent transfusions, different formulae had to be used, presumably because of the different rheological properties of adult, rather than fetal, blood in the fetal circulation. Bilardo et al. measured mean velocity in the common carotid artery of 12 previously untransfused anemic fetuses immediately before cordocentesis 26. There was a significantassociation between the degree of fetal anemia and the increase in blood velocity. The authors speculated that this increase in common carotid artery velocity reflected increased cardiac output associated with fetal anemia, rather than a chemoreceptormediated redistribution in blood flow, as seen in hypoxemic growth-restricted fetuses 27.

Vyas et al ., in a study of 24 previously untransfused, non-hydropic fetuses from red cell isoimmunized pregnancies at 18–35 weeks of gestation, reported a significant correlation between an increase in mean velocity in the middle cerebral artery and the degree of fetal anemia measured in samples obtained by cordocentesis 12. In an extended series of 95 previously untransfused fetuses undergoing cordocentesis for rhesus disease, there was a significant association between the increase in mean velocity in the middle cerebral artery with the degree of fetal anemia 16. In an additional series of 212 fetuses that had a transfusion 2–3 weeks previously, the relation between blood velocity and anemia was weaker 16. Mari et al . found a significant association between the peak systolic velocity in the middle cerebral artery and fetal hematocrit at cordocentesis. In a prospective study of 16 fetuses from isoimmunized pregnancies, they found that all the anemic fetuses had peak velocity values above the normal mean for gestation, whereas none of the fetuses with peak velocity below the normal mean was anemic 28. On the basis of these results, they suggested that, in the management of isoimmunized pregnancies, the indication for cordocentesis should be a peak systolic velocity above the normal mean for gestation. These results were confirmed in a multicenter study involving 111 fetuses from isoimmunized pregnancies; all moderately or severely anemic fetuses had increased peak velocity in the middle cerebral artery 29.

Steiner et al . performed 112 fetal blood samplings by cordocentesis in 33 cases with rhesus isoimmunization and found that the mean peak systolic aortic velocity of anemic fetuses was significantly higher than that of unaffected fetuses 30. Furthermore, there was a good correlation between delta peak velocities and delta hematocrits for the first procedure. Bahado-Singh et al. examined the main splenic artery waveforms in 22 nonhydropic fetuses from red cell isoimmunized pregnancies 31. The deceleration angle between the line describing the average slope during the diastolic phase of the cycle and the vertical axis was measured and expressed in multiples of the median (MoM) for gestational age. A decrease in the deceleration angle was associated with fetal anemia and, at a threshold deceleration angle of < 0.60 MoM, the sensitivity for severe anemia (hemoglobin deficit of 5 g/dl) was 100%, with an 8.8% false-positive rate. It was concluded that all cases of severe anemia could be identified before the development of hydrops, and, if, in the management of red cell isoimmunization, cordocentesis is only carried out if the deceleration angle is < 0.60 MoM, then the need for cordocentesis would decrease by more than 90% 31 .

The findings of increased blood velocity in the fetal arteries with anemia (Figure 2 and Figure 3) are compatible with the data from the fetal cardiac Doppler studies. If it is assumed that, in anemia, the cross-sectional area of the fetal descending aorta and middle cerebral arteries does not change, the increased velocity would reflect an increase in both central and peripheral blood flow due to increased cardiac output. The decreased aortic velocity in some hydropic fetuses may be the consequence of cardiac decompensation, presumably due to the associated hypoxia and lactic acidosis and to the impaired venous return due to liver infiltration with hemopoietic tissue 2.
Figure 2: Blood velocity in the fetal thoracic aorta (left) and middle cerebral artery (right) in red cell isoimmunized pregnancies plotted on the appropriate reference range (mean, 95th and 5th centiles) for gestation. Fetal anemia is associated with a hyperdynamic circulation.
Figure 3: Flow velocity waveformin the fetal middle cerebral artery in a severely anemic fetus at 22 weeks (left) and in a normal fetus (right). In fetal anemia, blood velocity is increased
Blood velocity in fetal veins

Rightmire et al . measured the fetal inferior vena caval time averaged mean velocity immediately before the first intravascular fetal blood transfusion in 19 rhesus-affected pregnancies at 18–28 weeks of gestation 17. Although the velocity was higher than in non-anemic controls, there was no significant correlation with fetal hematocrit. In the same study, the intrahepatic umbilical venous velocity was not significantly different from non-anemic controls. In contrast, Kirkinen et al. examined 18 rhesus isoimmunized pregnancies within 4 days before delivery and reported that, in anemic fetuses, the volume flow in the intrahepatic umbilical vein was significantly increased due to both increased blood velocity and vessel diameter 32. Similarly,Warren et al. performed serial measurements of fetal blood flow in 51 rhesus isoimmunized pregnancies and reported that increased flow was associated with subsequent development of fetal hydrops or rise in amniotic fluid bilirubin concentration. It was postulated that the increased flow was the result of reduced blood viscosity due to the reduced hematocrit. Iskaros et al. performed serial measurements of umbilical vein maximal flow velocity and found that elevated velocities prior to delivery were predictive of the need for exchange blood transfusion 33. They concluded that pregnancies with a mild or no history of fetal anemia may be monitored by a combination of serial antibody quantification and Doppler measurement of umbilical vein maximal flow velocities. Oepkes et al ., in a study of 21 previously transfused fetuses from red cell isoimmunized pregnancies, reported increased peak systolic and time averaged maximum velocities in the ductus venosus before intravascular fetal blood transfusion, which returned to normal values the following day 34.

It was suggested that the increase in ductus venosus blood flow in anemic fetuses reflects increased venous return and therefore cardiac preload. Hecher et al. recorded flow velocity waveforms from the ductus venosus, right hepatic vein, inferior vena cava, middle cerebral artery and descending thoracic aorta from 38 red cell isoimmunized pregnancies and found that only the velocity in the thoracic aorta was significantly associated with the degree of fetal anemia 35. Furthermore, this study showed that heart failure is not the primary mechanism for the development of hydrops, but rather the end-stage of severe anemia, because the pulsatility of venous blood flow waveforms was not increased. Hydrops may be due to reduced colloid osmotic pressure, hypoxia-induced endothelial damage and increased permeability. Severe fetal anemia, with consequent cardiac failure, is associated with a reversed ‘a’ wave in the ductus venosus. Under these conditions, pulsations are also present in the venous portal system (which in normal fetuses is characterized by a continuous flow). The pulsatile pattern present in the venous system corresponds to findings in children with portal hypertension 36. Since, in fetal anemia, resistance to flow in the fetal circulation and placenta is unchanged, an increase of umbilical venous blood flow is in accordance with high cardiac output and elevated arterial velocities.
Hemodynamic changes following fetal blood transfusion


Warren et al. and Kirkinen et al. found that, immediately after a fetal intraperitoneal blood transfusion, there was a temporary increase in umbilical venous blood flow and subsequent gradual decrease from above to within the normal range 18,32. It was suggested that the gradual decrease in flow, coinciding with resolution of fetal ascites, was the result of absorption of the transfused blood and correction of the fetal anemia. Copel et al. measured impedance to flow in the uterine and umbilical arteries and peak velocity in the descending thoracic aorta immediately before and 12 hours after fetal blood exchange transfusion by cordocentesis; no differences were found 15. Doppler studies of impedance to flow in the umbilical artery before and soon after intravascular top-up transfusion provided conflicting results. In a study of 43 cases, Bilardo et al. found no significant changes 26. In contrast, Weiner and Anderson and Hanretty et al. reported a significant decrease in impedance immediately after fetal blood transfusion in 19 and 22 fetuses, respectively 37,38. It was postulated that simple needling of fetal blood vessels stimulates a humoral vasodilator mechanism. Supportive evidence was provided by the finding that fetal blood levels of vasoactive substances with vasodilatatory effects, like prostaglandins and atrial natriuretic peptide, are increased after an intravascular blood transfusion 39,40. However, as Welch et al. Pointed out, the possible changes in indices of impedance after an intrauterine transfusion may not be simply due to vasodilatation but due to the complex influences of altered fetal whole blood viscosity, increased number of scattering particles (red cells) and vasoactive compounds 41. Bilardo et al. performed fetal Doppler studies in 43 cases immediately before and within 30 minutes of an intravascular top-up transfusion 26. There was a significant decrease in mean blood velocity in both the descending thoracic aorta (Figure 4 ) and common carotid artery. Similarly, Mari et al. found that intrauterine transfusion is associated with a significant decrease in the peak velocity in the middle cerebral artery and this decrease is proportional to the increase in fetal hematocrit 42. These findings are likely to be the result of a decrease in cardiac output following the transfusion due to:

(1) Increased blood hemoglobin concentration and viscosity, and consequent decrease in venous return;

(2) Congestive heart failure due to overloading of the fetal circulation; or

(3) Cardio-inhibition due to increased baroreceptor activity.

Confirmatory evidence of a decrease in cardiac output following blood transfusion was provided by Rizzo et al.22. They measured left and right cardiac outputs before and at 15-min intervals for 2 hours after an intravascular top-up transfusion in 12 fetuses. After transfusion, there was a significant temporary fall in both right and left cardiac outputs. Furthermore, the E/A ratios in both the tricuspid and mitral valves were increased suggesting that cardiac preload was also increased. Within 2 hours after transfusion, both parameters had returned towards the normal range. The fall in cardiac output was significantly related to the amount of expansion of the fetoplacental volume due to the transfusion. The most likely explanation for these findings is that transfusion results in temporary cardiovascular overload. Animal studies have also shown that the fetal heart has very limited reserve capacity to increase its output in response to acute overload, and that massive increases in fetal blood volume are associated with a decrease in cardiac output. After transfusion, there is a rapid rate of fluid loss and this explains the rapid recovery in E/A ratios and cardiac output 43.

Figure 4: Flow velocity waveform in the fetal descending thoracic aorta in an anemic fetus demonstrating high velocities and Doppler ‘window’ for low velocities during systole (top). After blood transfusion, there is a decrease in peak systolic velocity and the Doppler ‘window’ has disappeared (bottom).
The short-lived nature of the hemodynamic effects of intravascular transfusion can also explain the findings of Mari et al. who reported that the middle cerebral artery PI, internal carotid artery PI and umbilical artery PI before and the day after fetal transfusion were not significantly different 44. Similarly, Copel et al., in a study of cardiac output at 12 hours after intravascular blood transfusion, found no significant differences from the pretransfusion levels 20.
CONCLUSIONS
  • In red cell isoimmunized pregnancies, placentation is normal and therefore indices of impedance to flow in the uterine and umbilical arteries are normal, irrespective of the severity of fetal anemia.
  • In red cell isoimmunized pregnancies, normal placental perfusion results in normal fetal blood pO2, pCO2 and pH and therefore there is no evidence of redistribution in the fetal circulation; the PI in the middle cerebral artery, thoracic aorta and renal arteries is normal.
  • In red cell isoimmunized pregnancies, the left and right cardiac outputs and blood velocity in the umbilical vein, middle cerebral artery, thoracic aorta, renal arteries and the fetal venous system are  ncreased in proportion to the degree of fetal anemia. The most likely mechanism for the hyperdynamic circulation of anemic fetuses is decreased blood viscosity, leading to increasedvenous return and cardiac preload.
  • In red cell isoimmunized pregnancies, fetal heart failure is not the primary mechanism for the development of hydrops. However, severe anemia with consequent end-stage cardiac failure may be associated with high pulsatility or even reversed ‘a’ wave in the ductus venosus and pulsations in portal sinus.
  • In red cell isoimmunized pregnancies, intravascular fetal blood transfusion results in temporary cardiovascular overload with a temporary fall in both right and left cardiac outputs.
 
REFERENCES

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2. Nicolaides KH, Thilaganathan B, Rodeck CH, Mibashan RS. Erythroblastosis and reticulocytosis in anemic fetuses. Am J Obstet Gynecol 1988;159:1063–5

3. Nicolaides KH, Snijders RJM, Thorpe-Beeston JG, Van den Hof MC, Gosden CM, Bellingham AJ. Mean red cell volume in normal, small and anemic fetuses. Fetal Therapy 1989;4:1–13

4. Nicolaides KH. Studies on fetal physiology and pathophysiology in rhesus disease. Semin Perinatol1989;13:328–37

5. Soothill PW, Nicolaides KH, Rodeck CH, Bellingham AJ. The effect of replacing fetal with adult hemoglobin on the blood gas and acid–base parameters in human fetuses. Am J Obstet Gynecol 1988; 158:66–9

6. Soothill PW, Lestas AN, Nicolaides KH, Rodeck CH, Bellingham AJ. 2,3-Diphosphoglycerate in normal, anaemic and transfused human fetuses. Clin Sci 1988;74:527–30

7. Soothill PW, Nicolaides KH, Rodeck CH, Clewell WH, Lindridge J. Relationship of fetal hemoglobin and oxygen content to lactate concentration in Rh isoimmunized pregnancies. Obstet Gynecol 1987;69:268–71

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16. Nicolaides KH, Kaminopetros P. Red-cell isoimmunization. In Pearce M, ed. Doppler Ultrasound in Perinatal Medicine. Oxford: Oxford University Press, 1992;244–57

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40. Panos MZ, Nicolaides KH, Anderson JV, Economides DL, Rees L, Williams R. Plasma atrial natriuretic peptide: response to intravascular blood transfusion. Am J Obstet Gynecol 1989;161: 357–61

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Doppler in Obstetrics
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