Ultrasound Scores for Safe Detection of Severe Fetal Anemia

LEIDEN, The Netherlands, July 12 -- Noninvasive Doppler ultrasonography is superior to traditional amniocentesis for detecting severe hemolytic fetal disease in Rh-alloimmunized pregnancies, according to an international study.

The standard test to evaluate the need for fetal transfusion in hemolytic disease is serial amniocentesis to determine bilirubin levels in amniotic fluid, but although this test is accurate, amniocentesis caries risks of membrane rupture, infection, worsening of sensitization, and fetal loss, researchers wrote in the July 13 issue of the New England Journal of Medicine.

Doppler ultrasonographic measurement of peak velocity of systolic blood flow in the middle cerebral artery also predicts severe fetal anemia, but until now this test has not been rigorously evaluated in comparison with the amniotic-fluid test, said Dick Oepkes, M.D., at Leiden University here with colleagues here and at the University of Toronto.

In a prospective, international, multicenter study carried out by the Diagnostic Amniocentesis or Noninvasive Doppler (DIAMOND) Study Group, the researchers included women with RhD- Rhc- RhE- or Fy^a- alloimunized pregnancies with indirect antiglobulin titers of at least 1:64 and antigen-positive fetuses.

Of 165 fetuses, 74 had severe anemia. For the detection of severe fetal anemia, Doppler ultrasonography of the middle cerebral artery had a sensitivity of 88% (95% confidence interval, 78% to 93%), a specificity of 82% (CI, 73% to 89 %), and an accuracy of 85% (CI, 79% to 90%).

Amniotic-fluid ?OD₄₅₀ had a sensitivity of 76% (CI, 65% to 84%), a specificity of 77% (CI, 67% to 84%), and an accuracy of 76% (CI, 69% to 82%).

Doppler ultrasonography was more sensitive, by 12 percentage points (CI, 0.3 to 24.0), and more accurate, by nine percentage points (CI, 1.1 to 15.9), than measurement of amniotic-fluid ?OD₄₅₀, the researchers reported.

These results showed that Doppler measurement was significantly more accurate and sensitive than amniotic-fluid ?OD₄₅₀ measurement, Dr. Oepkes and colleagues said. "Given the invasive nature of amniocentesis and the associated risks, these data support the use of the noninvasive Doppler test in the evaluation of Rh-alloimmunized pregnancies," they wrote.

One strength of this study, the researchers said, is that it included clinicians in 10 centers in Europe and North America, all using their own standard protocols for the management of these pregnancies, except for the addition of the ultrasound procedure. The results, therefore, are generalizable. This study was not aimed at pregnancies with mild Rh alloimmunization, they added.

Although the Doppler technique can replace amniocentesis, it is important to note that its sensitivity is not 100%, Dr. Oepkes' team said. All studies, including this one, that have found ultrasonography highly accurate for this purpose were conducted in specialized referral centers by experienced clinicians and ultrasonographers. These women should be cared for in centralized facilities and should undergo serial complete fetal ultrasonographic examinations by experts in fetal medicine, the investigators added.

On the basis of smaller studies that found Doppler ultrasonography highly accurate for this purpose, most centers have gradually implemented a less invasive strategy for the management of these high-risk pregnancies, the researchers wrote. "The results of our large prospective study confirm that such a strategy is justified," they concluded.

In an accompanying editorial, Kenneth Moise, Jr., M.D., of the University of North Carolina at Chapel Hill, noted that the threshold for fetal anemia in this study was 5% to 10% higher between 18 and 28 weeks' gestation than that reported in an earlier study. This difference does no invalidate the current comparisons, Dr. Moise wrote, but the level of sensitivity reported here may appear to be better as a result.

Because Dr. Oepkes' team used a single Doppler measurement and a single ?OD_450, further investigation is warranted to assess whether serial measurements in the middle cerebral artery could improve sensitivity, he said.

The current results support the hypothesis that Doppler values may replace amniocentesis in the management of these pregnancies. But there are exceptions, he said. "Early experience has indicated the need for dual testing until a perinatal center has mastered the technique," he wrote. "In addition, referral to a distant perinatal center with experience in the use of the Doppler technique may not be practical for weekly testing."

Nevertheless, he concluded, the data in this study, along with evidence from other studies, "suggest that the time has come to put our needles aside when evaluating affected fetuses."

Dr. Moise reports having received consulting fees from Sequenom and Ortho-Clinical Diagnostics and grant support from Sequenom.