Utku Oz

Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization

Background Invasive techniques such as amniocentesis and cordocentesis are used for diagnosis and treatment in fetuses at risk for anemia due to maternal red-cell alloimmunization. The purpose of our study was to determine the value of noninvasive measurements of the velocity of blood flow in the fetal middle cerebral artery for the diagnosis of fetal anemia. Methods We measured the hemoglobin concentration in blood obtained by cordocentesis and also the peak velocity of systolic blood flow in the middle cerebral artery in 111 fetuses at risk for anemia due to maternal red-cell alloimmunization. Peak systolic velocity was measured by Doppler velocimetry. To identify the fetuses with anemia, the hemoglobin values of those at risk were compared with the values in 265 normal fetuses. Results Fetal hemoglobin concentrations increased with increasing gestational age in the 265 normal fetuses. Among the 111 fetuses at risk for anemia, 41 fetuses did not have anemia; 35 had mild anemia; 4 had moderate anemia; an...

Accurate prediction of fetal hemoglobin by Doppler ultrasonography.

OBJECTIVE To assess the feasibility of using the middle cerebral artery peak systolic velocity (MCA‐PSV) to predict the actual value of fetal hemoglobin in fetuses undergoing a first cordocentesis for detection of anemia caused by maternal red cell alloimmunization. METHODS Doppler velocimetry of the MCA‐PSV was performed in 18 fetuses before an initial cordocentesis. Hemoglobin and MCA‐PSV values were expressed as multiples of the median to adjust for the changes that both parameters demonstrate with gestational age. In each fetus we determined: 1) the expected (using a cubic mathematical function describing the correlation between fetal hemoglobin and MCA‐PSV) and the observed (determined at the time of the cordocentesis) hemoglobin value; and 2) the percentage differences between the expected and the observed hemoglobin values. RESULTS Gestational age at the time of the Doppler study ranged from 19 to 31 weeks. On 15 occasions, the fetuses demonstrated anemia. A quadratic relationship was found between the hemoglobin multiples of the median and the percentage differences between the expected and the observed hemoglobin values. As the values of hemoglobin decreased, the percentage difference between expected and observed values significantly decreased (R2 = 0.48, P < .05). The cubic model estimated fetal hemoglobin well in severely anemic fetuses and less well when the fetus was not anemic. CONCLUSION Doppler measurement of the MCA‐PSV appears to be a valuable tool for estimating hemoglobin concentration in fetuses at risk for anemia. The correlation between hemoglobin and MCA‐PSV becomes more accurate as the severity of anemia increases.

Fetal splenic size in anemia due to rh-alloimmunization

Objective To determine whether fetal splenic enlargement predicts anemia in Rh-alloimmunized nonhydropic singleton fetuses. Methods Splenic circumference was measured before funipuncture in 21 singleton pregnancies on 47 occasions. The spleen was imaged in an axial section of the fetal abdomen close to the level used for measurement of the abdominal circumference. The splenic length and width were measured and the circumference calculated by the formula (length and width × 1.57). One measurement per patient was used for each analysis. Splenic circumference was measured and expressed as multiples of the normal median (MoM) for gestational age. One hundred twenty-one cases were used to provide cross-sectional normative data. The expected median splenic circumference values were derived from a normal group. Fetal anemia was defined as hemoglobin deficit, ie, mean hemoglobin concentration for gestation minus the measured value. Anemia was defined as hemoglobin deficit exceeding 2 g/dL, and severe anemia as hemoglobin deficit exceeding 5 g/dL. Receiver operator characteristics curves for the prediction of anemia using different splenic circumference (MoM) values were constructed. Results Splenic circumference was an excellent predictor of severe anemia in cases with no prior transfusion: sensitivity 100% and specificity 94.7% (area under the curve = .97, P < .03). The measurement did not correlate significantly with severe anemia in the group with prior transfusion (area under the curve = .73, P = .19). Conclusion Splenomegaly is sensitive for the detection of severe anemia in nonhydropic Rh sensitized cases without prior transfusion. The splenic enlargement could be explained by extramedullary erythropoiesis.

Urinary screening tests for fetal Down syndrome: II. Hyperglycosylated hCG

Hyperglycosylated hCG is a form of hCG with more complex oligosaccharide side chains. A specific immunoassay was developed to measure hyperglycosylated hCG. Levels were measured in urine samples from 1157 women between 11 to 22 weeks of gestation, undergoing genetic analysis because of advanced maternal age. Values were normalized to urine creatinine concentration and plotted against gestational age, median values were determined and multiples of the control median (MoM) calculated. The median MoM and log standard deviation (log SD) of the 1134 control samples was 1.0 and 0.47, and of the 23 Down syndrome cases was 7.8 and 0.48, respectively. This indicated a 7.8‐fold increase in hyperglycosylated hCG levels in Down syndrome cases.

A new splenic artery Doppler velocimetric index for prediction of severe fetal anemia associated with Rh alloimmunization.

OBJECTIVE We developed a new Doppler index for the noninvasive prediction of severe fetal anemia by means of Doppler velocimetry of the main splenic artery. STUDY DESIGN Doppler velocimetry of the main splenic artery was performed in 85 healthy fetuses and in 22 nonhydropic study case patients (41 measurements) at risk for anemia from Rh sensitization. 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. Severe anemia was defined as a hemoglobin deficit (mean hemoglobin for gestational age minus measured hemoglobin) >/=5 g/dL. Anemia overall was defined as a hemoglobin deficit >/=2 g/dL. RESULTS Mean gestational age at cordocentesis was 28.6 weeks. Severe anemia was noted on 7 occasions (12.6%) and anemia was noted on 21 (51.2%) occasions. There was a significant correlation between deceleration angle and hemoglobin deficit >/=2 g/dL (r = 0.5763, P <.0001) and also with hemoglobin deficit >/=5 g/dL (r = 0.6418, P <.0001). At deceleration angles <0. 90 MoM, a 90.5% sensitivity and a 30% false-positive rate were achieved for anemia detection. At a threshold deceleration angle of <0.60 MoM, the sensitivity for severe anemia was 100%, with an 8.8% false-positive rate. CONCLUSION We report a new and sensitive Doppler velocimetric technique for predicting severe anemia. By means of splenic artery velocimetry, all cases of severe anemia could be identified before the development of hydrops, with a >91% reduction in the rate of cordocentesis.

Urinary screening tests for fetal Down syndrome: I. Fresh β‐core fragment

Variable results have been reported using urine β‐core fragment as a marker for fetal Down syndrome. Initial studies by Cuckle et al. (1994) and Canick et al. (1995) indicated that β‐core fragment was an outstanding marker, detecting >80 per cent of Down syndrome cases. Since these reports, widely varying results have been published, indicating between 20 per cent and 66 per cent detection of cases at 5 per cent false‐positive rate. The wide variation in the reported data has led to a loss of enthusiasm for this marker as a useful test for Down syndrome screening.

Splenic artery Doppler peak systolic velocity predicts severe fetal anemia in rhesus disease.

OBJECTIVE We sought to determine whether main splenic artery Doppler peak systolic velocity predicts severe anemia in the rhesus-alloimmunized fetus. STUDY DESIGN Splenic artery Doppler peak systolic velocity was obtained before cordocentesis in rhesus-alloimmunized fetuses. Normative values for mean peak systolic velocity based on gestational age were obtained cross-sectionally from a separate group of 144 normal fetuses. The peak systolic velocity values in the study group were expressed as multiples of the median for gestation, and threshold values were used as a screening test for severe anemia. The hemoglobin deficit was defined as mean hemoglobin for gestation minus measured hemoglobin. A hemoglobin deficit value of > or =5 g/dL was used to define severe anemia. We used the peak systolic velocity to screen for severe anemia in the overall study group and the subgroups with or without prior transfusions. RESULTS The study population consisted of 26 singleton nonhydropic fetuses in which cordocentesis and Doppler measurements were performed on a total of 55 occasions. The mean gestational age and standard deviation at cordocentesis was 29.6 +/- 4.0 weeks. Severe anemia was noted in 20% of fetal cord blood specimens obtained. On the basis of a receiver operating characteristic curve, a peak systolic velocity of > or =1.4 multiples of the median had a detection rate of 100%, with a false-positive rate of 20.8% in the subgroup with no prior transfusion (relative risk, 4.8; 95% confidence interval, 2.2-10.5). For peak systolic velocity threshold of > or =1.50 multiples of the median, corresponding values in the group with one prior transfusion were 80% and 12.5%, respectively (relative risk, 2.5; 95% confidence interval, 1.2-5.3). There was no risk of severe anemia with a peak systolic velocity below the median for gestation. CONCLUSION Fetal hydrops is rare, with a hemoglobin deficit of <5 g/dL. In the first such report the main splenic artery peak systolic velocity was noted to be a strong predictor of severe anemia. For the overall population, all such instances could be diagnosed while cordocentesis was performed 22.7% of the time. There is no risk of severe anemia with Doppler peak systolic velocities below the median for gestational age. The measurement is easily obtained and should be investigated as a clinical tool for minimizing the necessity for cordocentesis.

Midtrimester urine human chorionic gonadotropin β-subunit core fragment levels and the subsequent development of pre-eclampsia☆☆☆★

OBJECTIVE Our purpose was to determine whether midtrimester maternal urine human chorionic gonadotropin beta-subunit core fragment predicts later pre-eclampsia. STUDY DESIGN Urine beta-core fragment levels standardized to spot creatinine concentration and expressed as multiples of the median were prospectively determined in 347 midtrimester singleton pregnancies undergoing genetic amniocentesis. All women considered in the analysis were white and nonsmokers. Obstetric chart review was undertaken after delivery to identify cases in which pre-eclampsia developed. The risk of pre-eclampsia at different threshold levels of beta-core fragment of human chorionic gonadotropin was determined. RESULTS The median maternal age was 36.0 years, with a median gestational age at urine collection of 16.0 weeks. The median level of the beta-core fragment of human chorionic gonadotropin was 1385.5 ng/mg of creatinine in those with pre-eclampsia, whereas that in those without pre-eclampsia was 1061.2 ng/mg. The difference was significant (Mann-Whitney U test, P = .03). A significant linear association was found between the beta-core fragment concentration and the risk of pre-eclampsia (Mantel-Haenszel test of linear association, P = .03). The relative risk and 95% confidence interval of subsequent pre-eclampsia increased from 2.07 (1.06 to 4.05) at beta-core fragment levels of human chorionic gonadotropin > or = 2.0 multiples of the median to 5.17 (1.95 to 13.7) at > or = 4.0 multiples of the median. CONCLUSION Clinically normal patients with elevated midtrimester levels of urine beta-core fragment of human chorionic gonadotropin are at increased risk for the subsequent development of pre-eclampsia. The clinical value of this urine analyte as a marker for pre-eclampsia needs to be further investigated.

Gestational age standardized nuchal thickness values for estimating mid-trimester Down's syndrome risk.

OBJECTIVE Our aim was to develop gestational age standardized indices of fetal nuchal thickening. In addition, we wanted to develop a method for combining nuchal thickness data with maternal age for calculating individual Downs syndrome risk. METHODS Nuchal thickness was measured prospectively in pregnancies undergoing genetic amniocentesis. A regression equation for expected median nuchal thickness based on the biparietal diameter (BPD) was developed. Nuchal thickness values were expressed as multiples of the median (MoM). Additionally, a new parameter, percentage increase in nuchal thickness (PIN) (measured minus expected nuchal thickness) X100/expected nuchal thickness, was used. Receiver operator characteristics curves for Downs syndrome detection based on nuchal thickness values expressed as MoM, PIN, and in mm were compared. Log10 transformation of MoM data resulted in a Gaussian distribution, and the Downs syndrome likelihood ratios were calculated based on the heights of the Gaussian curves. Likelihood ratios were also calculated based on PIN values. The screening efficiency of maternal age alone was compared to age plus MoM, and age plus PIN values by multiplying age-related risk by the likelihood ratio corresponding to the given nuchal thickness MoM or PIN values. RESULTS There were 3,574 chromosomally normal and 50 Downs syndrome fetuses in the study. Both PIN and MoM values for nuchal thickness were closely correlated (R = 1.00, P<0.001) and each was poorly correlated with gestational age (R = 0.018, P = 0.28). The Downs syndrome screening efficiency of PIN, MoM, and nuchal thickness values in mm were not significantly different. The addition of nuchal thickness data to maternal age-related risk significantly improved the Downs syndrome screening efficiency: Area under the ROC curve for maternal age risk = 0.58, maternal age + PIN area = 0.79 (P<0.001 compared to maternal age alone) and for maternal age + MoM = 0.77 (P<0.005 compared to maternal age alone). CONCLUSIONS The development of gestational age standardized nuchal thickness indices makes it possible to combine ultrasound and maternal age-related risk to derive individual Downs syndrome odds.

Urine hyperglycosylated hCG plus ultrasound biometry for detection of Down syndrome in the second trimester in a high-risk population

Objective To evaluate measurement of levels of urine hyperglycosylated hCG, a form of hCG with abnormally branched oligosaccharide side chains, in conjunction with ultrasound biometry for Down syndrome risk prediction in an at-risk group. Method We prospectively measured urine hyperglycosylated hCG levels, humeral length, and nuchal thickness in women who had second-trimester amniocentesis. Urine hyperglycosylated hCG levels were measured by a two-step enzyme-immunometric assay using monoclonal antibody β152. Humeral length, nuchal thickness, and hyperglycosylated hCG values were expressed as multiples of the median, and the Down syndrome screening efficiency of the three analytes plus age was determined. A receiver operating characteristic (ROC) curve was generated, and the area under the curve was used to assess the Down syndrome screening performance of the algorithm. Results There were 23 cases of Down syndrome among 1016 singleton pregnancies. Mean gestational age (± standard deviation) was 16.1 ± 1.2 weeks at the time of amniocentesis. Mean maternal age was 37.1 ± 3.2 years. Biometry and measurement of hyperglycosylated hCG levels had a 91.3% detection rate at a 3.2% false-positive rate and a 100% detection rate at a 10.7% false-positive rate. The area under the ROC curve was 0.986 (P < .001), and that for measurement of hyperglycosylated hCG levels plus age was 0.941 (P < .001). The area under the curve was significantly larger with combined biochemical and biometry markers compared with measurement of hyperglycosylated hCG levels plus age alone (P < .02), proving that the former was superior to the latter. Conclusion A new Down syndrome biochemical marker combined with ultrasound biometry had a high screening efficiency in a high-risk group. All cases of Down syndrome in this study population would have been detected at an amniocentesis rate of less than 10.7%. Our results appear superior to those found with other second-trimester algorithms. The combination is promising as an alternative to “automatic” genetic amniocentesis in women of advanced maternal age and other high-risk groups.