Doppler velocimetry of fetal middle cerebral artery predicts anemia [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Among fetuses at risk for maternal red cell alloimmunization, peak systolic velocity in the middle cerebral artery is a sensitive predictor of moderate or severe fetal anemia.

Original Date of Publication: January 2000

Study Rundown: Maternal red cell alloimmunization is a morbid immunogenic phenomenon that complicates less than 1% of pregnancies but is associated with a high risk of fetal anemia. Maternal alloimmunization results when a pregnant woman previously sensitized to a paternally-derived red cell antigen is re-exposed in pregnancy by a fetus that carries this paternally-derived red cell antigen. In response, maternal antibodies are produced that then cross the placenta, bind to antigens on fetal red blood cells and cause hemolysis. In severe cases, hemolysis can progress to severe fetal anemia, hydrops fetalis and even fetal death.

As of the late 1990s, women at risk for alloimmunization underwent invasive testing via serial cordocentesis, the standard of care, or amniocenteses to diagnose fetal anemia. Cordocentesis permitted direct measurement of fetal hemoglobin but also exposed women to a 1-2% risk of fetal loss, 50% risk of fetal-maternal hemorrhage with subsequent worsening of alloimmunization. Amniocentesis carried less risk but is unreliable at predicting the degree of fetal anemia prior to 27 weeks gestation due to the wide variation in bilirubin levels in fetal amniotic fluid. Researchers hypothesized that measuring peak systolic velocity in a fetal cerebral artery might permit reliable yet noninvasive diagnosis of fetal anemia. The middle cerebral artery responds rapidly to ischemia, is conveniently located between the ultrasound beam and the direction of blood flow, and velocity measurements of this artery are associated with minimal intra and interobserver variability. A prior study showed that peak systolic velocity through the fetal middle cerebral artery, as measured by ultrasound, was increased in anemic infants. In the present work, researchers compared invasive cordocentesis to peak systolic middle cerebral artery velocimetry among infants at risk for maternal alloimmunization to diagnose fetal anemia.

This landmark study demonstrated that peak systolic velocity through the middle cerebral artery is a sensitive predictor of moderate or severe fetal anemia in pregnancies at risk for maternal red cell alloimmunization. Findings allowed for noninvasive diagnosis of fetal anemia and thusprevented an estimated 140 pregnancy losses associated with cordocentesis each year since publication. Strengths included multicenter study, concomitant measurement of hemoglobin by both direct (cordocentesis) and indirect (Doppler velocimetry) methods, and use of a control population. Limitations included small sample size to evaluate variation in velocity associated with diagnosis of fetal hydrops (n = 11).

Click to read the study in NEJM

Dr. Alan Peaceman, MD, talks to 2 Minute Medicine: Northwestern University School of Medicine; Chief, Division of Obstetrics and Gynecology-Maternal Fetal Medicine.

“This study demonstrated that increased peak systolic velocity in the middle cerebral artery is a sensitive predictor of moderate or severe fetal anemia. Findings support the use of noninvasive Doppler velocimetry for diagnosis of fetal anemia in pregnancies at risk for maternal red cell alloimunization and prevent fetuses with mild anemia from exposure to the morbidity and mortality associated with invasive testing.”

In-Depth [cross-sectional study]: A total of 111 fetuses at risk for anemia due to maternal red cell alloimmunization underwent measurement of hemoglobin concentration via invasive cordocentesis and also via noninvasive measurement of middle cerebral artery peak systolic velocity using doppler velocimetry. Hemoglobin values in at-risk infants were compared to the hemoglobin values of 265 normal fetuses in this comparative cross-sectional study. The outcome of interest was moderate fetal anemia, defined as hemoglobin <0.65 times the median hemoglobin concentration in normal fetuses and severe anemia, defined as <0.55 times the median.

Among infants at risk for anemia related to maternal alloimmunization, 32% had mild anemia, 4% had moderate anemia and 28% had severe anemia. All fetuses with moderate or severe anemia had peak systolic velocity values greater than 1.5 times the median, conferring 100% sensitivity and 100% negative predictive value. The relationship between multiples of the median of peak systolic velocity and of moderate or severe anemia was significant even in mothers with Kell sensitization (p < 0.001).

Image: PD

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