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Middle cerebral artery Doppler for the prediction of fetal anaemia in cases without hydrops: a practical approach

Fetal Medicine Research Unit, St Michael's Hospital, University of Bristol, Southwell Street, Bristol BS2 8EG, UK

Correspondence: Dr Phillipa Kyle, MD, MRCOG, Consultant in Fetal Medicine

	Abstract

Top Abstract Introduction Subjects and methods Results Discussion References

 
The aim of this study was to assess the value of the middle cerebral artery (MCA) Doppler time-averaged mean velocity (TAMV) for the prediction of fetal anaemia in at-risk cases without ultrasound evidence of hydrops. The study included 35 pregnant women with non-hydropic fetuses and with known red cell antibodies, referred either because of a rapid increase in antibody levels or because of a previous history of a severely anaemic fetus or neonate. After full ultrasound examination of the fetus, MCA Doppler TAMV was measured and, if severe anaemia was suspected, fetal blood sampling by cordocentesis was performed with blood ready for intrauterine transfusion if necessary. Of the 35 fetuses, 28 were anaemic and 7 had a haemoglobin (Hb) value within the normal range. There was a strong negative correlation between the MCA Doppler TAMV and the Hb values (correlation coefficient r=-0.65, p<0.0001). The mean MCA Doppler TAMV (z score) for fetuses with normal Hb was 1.55±1.68, while that for the anaemic fetuses was 4.06±1.38, (p<0.001). The sensitivity of the increased MCA Doppler TAMV to predict fetal anaemia in these cases was 96.4% and the specificity was 71.4%. These data confirm that MCA Doppler TAMV is significantly correlated to fetal Hb. This non-invasive investigation can be reliable in predicting anaemia in cases in which the need to sample fetal blood is not certain, therefore delaying invasive testing until treatment is likely to be required.

	Introduction

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With the established use of post-natal anti-D prophylaxis for rhesus (Rh) negative women, together with its increasing use for routine antenatal prophylaxis, the incidence of Rh-D sensitization has dramatically fallen [1]. However, this condition, together with sensitization against other red cell antigens, still affects a large number of pregnancies every year, with significant health and financial implications. Women with rising red cell antibody levels, with or without a history of a previously affected pregnancy, are usually referred to tertiary fetal medicine units for specialized management. The main challenge facing fetal medicine specialists today is not the skill required for invasive therapy, but rather the non-invasive monitoring of the disease so that its progress can be predicted to guide the need and timing of intrauterine transfusions to minimize unnecessary invasive testing.

The most accurate test to assess the degree of fetal anaemia, and thus the need for transfusion, is the fetal haemoglobin (Hb) measurement by fetal blood sampling. However, cordocentesis can cause an increase in antibody concentration [2, 3], is associated with approximately a 1% fetal loss rate [4] and is therefore not an appropriate first line investigation. Cordocentesis is best reserved for cases in which severe fetal anaemia is already suspected and intrauterine transfusion is likely to follow. Amniocentesis to assess the bilirubin Delta OD450 levels in the amniotic fluid has been the traditional method to indirectly assess haemolysis. As the amniocentesis needle usually avoids the placenta, the risk of boosting the antibody level is lower than with cordocentesis [2], although the procedure still has small but significant risks of causing miscarriage or pre-term labour.

In recent years, several non-invasive methods for the prediction of fetal anaemia have been assessed, aiming to defer the use of invasive testing until transfusion is expected to be necessary [5–8]. The association of increased blood flow velocity in the fetal middle cerebral artery (MCA) with fetal anaemia [9] is the most promising of these non-invasive tests as has subsequently been reported [10–12]. The aims of this study were to investigate this association and to examine its usefulness in routine practice in cases where there are no other signs indicative of fetal anaemia such as hydrops.

	Subjects and methods

Top Abstract Introduction Subjects and methods Results Discussion References

 
The study included 35 pregnant women with red cell antibodies referred for assessment and management. Patients were mainly referred if there was an increase in antibody levels in the maternal serum, or if there was a previous obstetric history of an anaemic fetus or neonate. Assessment consisted of ultrasound examination for fetal biometry, exclusion of any structural abnormalities, liquor volume assessment, umbilical artery Doppler blood flow studies and Doppler blood flow velocity studies of the MCA. Hydrops was defined as fluid collection in body cavities or skin oedema, and hydropic fetuses were excluded from the study. If fetal anaemia was suspected, fetal blood sampling by cordocentesis was performed. The MCA Doppler studies were routinely performed in our unit as part of full assessment of fetuses at risk for anaemia. We included only the results from the initial blood sample, and no fetuses were entered in the study subsequent to a transfusion. Invasive intervention was performed on the patients' first visit in 29 cases. In the remaining six patients the picture obtained on the first visit did not indicate severe anaemia and follow-up was arranged. All patients whose assessment was more suggestive of worsening anaemia underwent cordocentesis on the second visit.

Doppler examination of the MCA was performed using a previously described technique [10]. To visualize the MCA, an axial section of fetal brain at the level of the biparietal diameter was obtained with the image including the thalami and cavum septum pellucidum. The transducer was then moved caudally towards the skull base until the circle of Willis was visualized and the MCA identified as its major lateral branch. Colour flow mapping was used to facilitate visualization of the vessel. The pulsed Doppler gate was located on the proximal one-third of the MCA, with the angle between the ultrasound beam and blood flow kept as close as possible to 0° and, in all cases, was less than 20°. The flow velocity waveform measurements were taken in the absence of marked fetal body and breathing movements, and usually two or three measurements were repeated and the most uniform waveforms used. We recorded the time-averaged mean velocity (TAMV). Examinations were performed using an Acuson Aspen or Acuson 128XP ultrasound machine (Acuson, Mountain View, CA). The MCA TAMV was defined as increased if the measurement was more than 2 standard deviations (SDs) above the mean for gestational age, using the normograms produced by Harrington et al [13].

Fetal blood sampling was performed by cordocentesis from the umbilical vein at the placental cord insertion with blood ready for fetal transfusion if necessary. Fetal blood was immediately examined for determination of the full blood count and, if anaemia was confirmed, intravascular transfusion was performed. Fetal anaemia was defined as Hb less than 2 SDs below the mean for gestational age [14].

All measurements obtained, including fetal Hb and MCA TAMV, were entered on the computer program ViewPoint Fetal Database (ViewPoint Version 3.22; Bildverarbeitung Gmbh, Wessling, Germany), which includes the normograms for gestational ages (Nicolaides 1993 [14] and Harrington 1995 [13], for fetal Hb and MCA TAMV, respectively). To correct for gestational age differences, all measurements were expressed as multiples of SD from the normal mean for gestational age (z score). Statistical analysis was performed using an SPSS program (SPSS for Windows, version 8.0; SPSS Inc., Chicago, IL). We tested for correlation between fetal Hb values and MCA TAMV using Spearman's rank correlation coefficient. The MCA TAMV was also compared between anaemic and non-anaemic fetuses using the Mann-Whitney U-test. Sensitivity and specificity of the increased MCA TAMV to predict fetal anaemia were tested using an exact binomial method in STATA version 6.0 (Stata Corp., College Station, TX).

	Results

Top Abstract Introduction Subjects and methods Results Discussion References

 
This study included 35 pregnant women with alloimmunized, non-hydropic fetuses. As expected, the majority of cases were sensitized to the D antigen (30 cases). Other sensitizing antigens included Kell and c antigens (two cases each) and the E antigen (one case). The median gestational age was 28 weeks (range 18–35 weeks) and the median patient age was 31 years (range 17–40 years). Only one patient was in her first pregnancy while all others were multiparous. Of the 35 fetuses, 28 were anaemic and 7 had normal Hb. There was a strong negative correlation between MCA TAMV and Hb values (correlation coefficient r=-0.65, p<0.0001) (Figure 1). The mean MCA TAMV (z score) for fetuses with normal Hb was 1.55±1.68, while that for anaemic fetuses was 4.06±1.38 (p<0.001). Figure 2 demonstrates the distribution of MCA TAMV values in both the anaemic and non-anaemic fetuses, showing the median, range and interquartile ranges for each group.

View larger version (10K): [in this window] [in a new window]   Figure 1 The correlation between the fetal middle cerebral artery (MCA) time-averaged mean velocity (TAMV) and the haemoglobin (Hb) values (z score). Correlation coefficient r=-0.65, p<0.0001. SDs, standard deviations.

View larger version (28K): [in this window] [in a new window]   Figure 2 The distribution of the middle cerebral artery (MCA) time-averaged mean velocity (TAMV) in non-anaemic and anaemic fetuses demonstrating the difference between the two groups. Non-anaemic fetuses; median 1.12, interquartile range 3.35, maximum value 4.1, minimum value -0.53. Anaemic fetuses; median 4.09, interquartile range 2.09, maximum value 6.42, minimum value 1.87.

	Discussion

Top Abstract Introduction Subjects and methods Results Discussion References

 
These data confirm that MCA TAMV is significantly increased in cases of fetal anaemia owing to red cell antibodies. The most likely physiological explanation for this is that anaemia is associated with both increased cardiac output, due to the hyperdynamic circulation, and a reduction in blood viscosity, both leading to increased blood flow velocity. These associations have initially been demonstrated in animal studies [15], and subsequently in human studies [16–18]. The MCA is particularly useful for such measurement as it is relatively easy to visualize and measure the waveform with a narrow angle between the ultrasound beam and direction of blood flow, approximating 0°.

The association between increased MCA blood flow velocity and fetal anaemia has been previously demonstrated using peak systolic velocity [10–12]. Although these studies demonstrated the same trend, data interpretation were complicated and, for various reasons, difficult to reproduce in other centres. First, each of these studies used their own institutional normal reference ranges for MCA blood flow velocity values and some have also produced their own normograms for fetal Hb or haematocrit values. The use of published, generally agreed, normograms was preferred for this study. These normograms are also the reference ranges available on the computer database commonly used by many fetal medicine units and in several obstetric ultrasound and fetal medicine textbooks. This would not only ensure reproducibility but also avoid any confusion regarding definition of normal ranges.

Second, the definition of "abnormal values" of MCA blood flow velocity was equally varied and sometimes confusing. One study [12] defined more than 1 SD above the mean as the cut-off between normal and abnormal values, while another study [10] used multiples of the standard error of estimation as a more precise statistical measurement. In a recent large multicentre study [11], fetal anaemia was defined as moderate if Hb was between 0.65 and 0.55 times the median for gestation, and severe if it was less than 0.55 times the median. Threshold values for MCA peak systolic velocity to detect fetal anaemia were 1.5 and 1.55 times the median for moderate and severe anaemia, respectively. The definitions used in all these studies might be well justified statistically and may also serve to improve the sensitivity of the test, but they are not commonly employed in clinical practice, thereby limiting widespread reproducibility and the application of this test as a practical and simple tool for non-invasive detection of fetal anaemia.

Of the 35 fetuses in our study, only 7 (20%) had a normal Hb on first assessment, which demonstrates the usefulness of the test to minimize unnecessary invasive testing. Two of these non-anaemic fetuses had increased MCA TAMV (false positives) and their Hbs were -1.36 SDs and -1.47 SDs of the means for gestational age. Although these figures are classified as within the normal range they are clearly low normal and, since in both these patients the fetal blood had a highly positive direct Coomb's test, fetal anaemia was likely to follow soon. The other fetuses with normal initial Hb were sampled in spite of a normal MCA TAMV as the clinical picture was suggestive of fetal anaemia, either because of a sharp rise in antibody levels or in view of previous obstetric history. In contrast, only one anaemic fetus had a normal MCA TAMV (false negative), and was also sampled because of a rapid rise in antibody levels. Furthermore, as far as can be known, no babies with normal MCA Doppler readings who had not therefore proceeded to fetal blood sampling were born unexpectedly anaemic.

As the presence of fetal hydrops in women with known red cell antibodies, particularly in association with a recent sudden rise in antibody levels, is almost certainly owing to severe anaemia, hydropic fetuses were excluded from this study. This is because we wished to assess how effective the measurement of MCA Doppler velocity is at predicting fetal anaemia in borderline cases, in which the decision to sample the fetal blood is not clear. MCA TAMV, and not the peak systolic velocity, which has been reported by recent MCA Doppler studies [10–12] was used because it has been practice in our unit to record this parameter since it was originally reported by Vyas et al in 1990 [9]. More recently, however, both measurements have been routinely recorded on our database.

This study further confirmed that MCA blood flow velocity Doppler can be a reliable non-invasive test for the detection of fetal anaemia in at-risk fetuses without hydrops. However, no non-invasive test is 100% accurate in all cases, and so the assessment of patients with red cell antibodies should be comprehensive and include all possible relevant information, including obstetric history and rate of change of antibody levels.

	Acknowledgments

 
Special thanks to Rosemary Greenwood, Medical Statistician, Research and Development Unit, Bristol Royal Infirmary for her help with statistical analysis.

Received for publication December 20, 2001. Revision received May 15, 2002. Accepted for publication May 23, 2002.

	References

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