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Obstetrics & Gynecology 2002;100:51-57
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Amniotic Fluid {Delta} OD 450 Values Accurately Predict Severe Fetal Anemia in D-Alloimmunization

Esther Sikkel, MD, Frank P. H. A. Vandenbussche, MD, PhD, Dick Oepkes, MD, PhD, Robertjan H. Meerman, BSc, Saskia Le Cessie, PhD and Humphrey H. H. Kanhai, MD, PhD

From the Department of Obstetrics and Gynecology, and Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands.

Address reprint requests to: Frank P. H. A. Vandenbussche, MD, PhD, Leiden University Medical Center, Department of Obstetrics, K6-32, P.O. Box 9600, 2300 RC Leiden, the Netherlands; E-mail: frank.vandenbussche{at}lumc.nl.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To assess the diagnostic accuracy of amniotic fluid {Delta} OD 450 values in the second and third trimesters of D-alloimmunized pregnancies.

METHODS: We searched our database for singleton D-alloimmunized pregnancies with nonhydropic fetuses, where amniocentesis was performed within 4 days of first fetal blood sampling. Amniotic fluid {Delta} OD 450 values were plotted on an extrapolated Liley’s chart. Sensitivity and specificity were calculated for two commonly used cutoff levels, Liley’s zone 3 and the upper third of Liley’s zone 2. Severe fetal anemia was defined as a hemoglobin concentration of more than 5 standard deviations below the normal mean for corresponding gestational age.

RESULTS: Seventy-nine pregnancies met our inclusion criteria. Overall accuracy of the extrapolated Liley’s curve in predicting severe fetal anemia was 75% (95% confidence interval [CI] 64, 84) for zone 3 and 86% (95% CI 77, 93) when the upper third of zone 2 was included. Sensitivity of {Delta} OD 450 values in Liley’s zone 3 or the upper third of Liley’s zone 2 was 95% (95% CI 74, 100) before and 98% (95% CI 89, 100) after 27 weeks.

CONCLUSION: Liley’s extrapolated curve predicts severe fetal anemia with reasonable accuracy and high sensitivity.

In 1961, Liley proposed amniotic fluid sampling to measure deviation of optical density at 450 nm ({Delta} OD 450) to predict life-threatening fetal anemia in the third trimester.1 After intrauterine intravascular transfusion became a relatively safe procedure as early as 18 weeks, the original Liley’s chart was extrapolated to the second trimester to also predict severe anemia there. This was done by linear extension of the two lines that divide Liley’s three zones.2–4 The American College of Obstetricians and Gynecologists (ACOG) recommends serial amniocentesis in pregnancies at risk, followed by intrauterine intravascular transfusion or early delivery when {Delta} OD 450 values are in Liley’s zone 3 or in the upper third of Liley’s zone 2 and rising.5 Several authors have proposed management schemes based on different cutoff values for {Delta} OD 450.6–12 Among these, the Queenan chart is the most popular.10 In 1986, Nicolaides et al concluded that {Delta} OD 450 values were unreliable as predictors of severe anemia in second-trimester pregnancies.13 Others also questioned the value of {Delta} OD 450 during the third trimester.8,14–16 These doubts applied both to Liley’s original chart and to modified versions.14 However, these studies included amniotic fluid samples that were taken more than a week before the "gold standard" blood sample, and included cases with Kell antibodies where anemia is partially caused by erythroid precursor damage and not merely by the results of hemolysis.17,18 These studies also included cases of hydrops fetalis, where {Delta} OD 450 is not only unreliable but also superfluous.19,20

A critical evaluation of the diagnostic performance of {Delta} OD 450 measurement is warranted because new non-invasive methods are being introduced to replace amniocentesis.21,22 These methods are based on the fact that blood viscosity, which declines along with hematocrit, is inversely related to maximum blood flow velocities in fetal vessels. The proponents of these Doppler methods claim great accuracy in the prediction of fetal anemia.22–25 As a first step in comparing amniocentesis and noninvasive Doppler, we evaluated the ability of {Delta} OD 450 values to predict severe fetal anemia.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The Leiden University Medical Center is the national referral center for the treatment of alloimmune fetal anemia in the Netherlands. Our methods for diagnosing and treating severe fetal anemia have been described previously.26 Briefly, patients with high antibody titers are followed with weekly ultrasound examinations for signs of incipient hydrops or fetal anemia. These signs include hepatosplenomegaly, cardiomegaly, placental thickening, decreased fetal movements, and increased maximum flow velocities in the descending aorta and intrahepatic umbilical vein.21 When severe anemia is suspected at or after 27 weeks, amniocentesis for {Delta} OD 450 is performed to avoid unnecessary fetal blood sampling. For the data in this study, we followed our center’s established procedure, performing the first intrauterine intravascular transfusion when {Delta} OD 450 was in zone 3, or in the upper third of zone 2 and rising.5 In some fetuses after 27 weeks and in most before 27 weeks, the decision to perform the first intrauterine intravascular transfusion was based on ultrasound findings alone. In these cases, when a transamniotic approach to the fetal umbilical vein was necessary, amniotic fluid was collected and {Delta} OD 450 measured for the purpose of this study. This procedure was approved by the hospital’s ethical committee, and in each case oral informed consent of the mother was obtained. The data of all patients were stored in our database (Paradox 9.0, Corel Corp., Ottawa, Canada). We searched this database for the period January 1988 to October 2000 for contemporaneous amniotic fluid and fetal blood samples that met the following criteria: they were taken from fetuses that were 1) rhesus D-alloimunized, 2) nonhydropic, 3) not previously transfused, 4) singleton, and 5) amniotic fluid samples were taken less than 4 days before fetal blood sampling.

Amniotic fluid samples (5–10 mL), protected from light during transport, were centrifuged at 1000 G for 10 minutes to remove vernix and erythrocytes. The absorption of the supernatant was measured at the wavelengths 365, 450, and 550 nm with an UltrospecPlus spectrofotometer (Amersham Pharmacia Biotech, Little Chalfont, UK). The bilirubin absorption, expressed as {Delta} OD 450, was calculated as the difference between the measured absorption at 450 nm and the background absorption at 450 nm. The latter was derived, as described by Liley, from the logarithmic function of the absorptions between 365 and 550 nm.1 Each {Delta} OD 450 was measured and entered into our database within an hour after amniocentesis. Only values at or after 27 weeks were used clinically. At intrauterine intravascular transfusion, a small portion of the initial fetal blood sample was used for on-the-spot measurement of hemoglobin concentration and mean red cell volume. Fetal hematocrit was used to calculate the volume of intravascular red cell transfusion.27 The remaining fetal blood of the initial sample was sent to our central laboratory for hematology and other measurements. These latter values were automatically entered into our database and checked by a specialized nurse. Statistical analysis was performed using SPSS 10.0 (SPSS Inc., Chicago, IL).

We copied Liley’s original chart1 and found that the upper line that defined zone 2 crossed the vertical lines corresponding with 27 and 41 weeks at {Delta} OD 450 of 0.260 and 0.077, respectively; the (parallel) lower line defining zone 2 crossed the vertical line corresponding with 27 weeks at 0.066. We then drew a third parallel line through the {Delta} OD 450 of 0.160 at 27 weeks, as the delineation of the upper third of zone 2 (2c). All three lines were extrapolated backwards in a linear fashion from 27 to 18 weeks. Standardized amniotic fluid {Delta} OD 450 was calculated by dividing the {Delta} OD 450 measurement by the value on the line between zones 1 and 2 for the corresponding gestational age. For example, a {Delta} OD 450 of 0.260 nm at 27 weeks and a {Delta} OD 450 of 0.141 at 34 weeks are both on the border between zones 2 and 3. Both correspond with a standardized {Delta} OD 450 of 3.94. The latter value is found by dividing the {Delta} OD 450 measurements (0.260 and 0.141) by the cutoff values on the line between zones 1 and 2 (0.066 and 0.036, respectively) for the corresponding gestational ages. In this way, the standardized {Delta} OD 450 is independent of gestational age and indicates how much the measured value was higher than the corresponding boundary value between zones 1 and 2. Standardized values above 3.94 correspond to Liley’s values in zone 3.

Normal fetal hemoglobin values increase during gestation. We used the reference values proposed by Nicolaides et al in 1988.28 These reference values were obtained from 210 fetuses, ranging from 17 to 40 weeks, and they have a constant standard deviation (SD) of 1 g/dL.28 For the purpose of this study, we defined severe anemia as hemoglobin concentrations more than 5 SD below the normal mean for gestational age. This cutoff was chosen because a higher cutoff would include fetuses in whom the need of treatment is not warranted, whereas a lower cutoff would include too many cases of hydrops fetalis, which would not only render the use of diagnostic amniocentesis redundant but would also worsen the prognosis significantly.29 Moderate anemia was defined as a hemoglobin concentration more than 2 SD but 5 SD or less below the normal mean for gestational age. Standardized fetal hemoglobin scores were defined as the number of SDs that the actual value deviated from the normal mean for gestational age.

Sensitivity, specificity, and overall accuracy (combined rate of true-positive and true-negative results) were calculated for different {Delta} OD 450 cutoffs (Liley’s zones 3 and 2c) in the prediction of severe anemia, together with their exact 95% confidence intervals (CIs). Separate analyses were done for gestational ages above and below 27 completed weeks. Pearson R2 was calculated between standardized {Delta} OD 450 and standardized hemoglobin. To study if this relation differed before and after 27 weeks, linear regression was performed with standardized hemoglobin as the outcome variable and standardized {Delta} OD 450 as the independent variable. The slopes of the regression lines before and after 27 weeks were compared by adding a dummy variable in the regression model, indicating whether the pregnancy was more than 27 weeks, and testing the significance of the interaction term between standardized {Delta} OD 450 and the dummy variable.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In the 13-year study period, 249 fetuses were treated for alloimmune anemia with one or more intrauterine intravascular transfusions; 139 of these were anti D-alloimmunized and nonhydropic, and 79 of them fulfilled our inclusion criteria of singletons with contemporaneous sampling of amniotic fluid and fetal blood at their first intrauterine intravascular transfusion. Mean gestational age of these 79 fetuses at the time of first intrauterine intravascular transfusion was 29 completed weeks (range 20–35), and mean hemoglobin concentration was 6.3 g/dL (range 3.1–13.2). Mean age of the 79 women was 32 years (range 23–44), and parity was 3.3 (range 2–14). There was one fetal and one neonatal death among these 79 cases. The fetal death occurred at 25 weeks because of an intrauterine infection after the third intrauterine intravascular transfusion. In this case, the first intrauterine intravascular transfusion (the data from which were used in this study) took place at 21 weeks. The neonatal death occurred after an emergency cesarean, 4 hours after the first intrauterine intravascular transfusion. This intrauterine intravascular transfusion took place at 35 weeks and was complicated by continuing leakage of blood from the cord at the puncture site.

Figure 1Go plots hemoglobin values of these 79 fetuses against their gestational age, compared with the normal range (mean ± 2 SD) of fetal hemoglobin concentration as established by Nicolaides et al28 as well as the -5 SD line that we used as the cutoff for severe anemia. Of the 79 fetuses included in this study, only one had a hemoglobin concentration in the normal range, 11 showed moderate anemia, and 67 had severe anemia at the time of first fetal blood sampling. Amniotic fluid {Delta} OD 450 values of the 79 fetuses are shown on the extrapolated Liley’s chart (Figure 2Go).



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  		Figure 1. Hemoglobin values of 79 nonhydropic rhesus D-alloimmunized fetuses at first blood sampling, plotted against their gestational age. The grey zone between the three upper ascending lines marks the limit of normal (mean ± 2 standard deviations) fetal hemoglobin concentrations. The lower line separates moderate (between -2 and -5 standard deviations) from severe (less than -5 standard deviations) fetal anemia.

Sikkel. Accuracy of {Delta} OD 450. Obstet Gynecol 2002.

 


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  		Figure 2. Amniotic fluid {Delta} OD 450 values of 79 nonhydropic rhesus D-alloimmunized fetuses at the time of first blood sampling, plotted in the extrapolated Liley’s curve. No anemia ({blacktriangleup}) corresponds with hemoglobin concentrations within the normal range (mean ± 2 standard deviations) for gestational age; moderate anemia ({diamondsuit}) corresponds with hemoglobin concentrations between 2 and 5 standard deviations below the normal mean; and severe anemia (O) corresponds with fetal hemoglobin concentrations more than 5 standard deviations below the normal mean. The vertical axis ({Delta} OD 450) has a logarithmic scale, and the horizontal axis (gestational age) has a linear scale. The vertical broken line is drawn at 27 weeks to divide Liley’s original chart from the extrapolated part. The descending broken line divides zone 2 in an upper third (2c) and two lower thirds (2a, 2b). Note that this upper third is on a visual and not on a logarithmic scale.

Sikkel. Accuracy of {Delta} OD 450. Obstet Gynecol 2002.

 
Figure 3Go shows the relationship between standardized hemoglobin values at the first intrauterine intravascular transfusion and contemporaneous standardized {Delta} OD 450 values of the 79 fetuses in our study. The linear correlation between standardized {Delta} OD 450 on a logarithmic scale and standardized hemoglobin was low (R2 = 0.096). Pearson R2 between {Delta} OD 450 and hemoglobin values was 0.315 for the samples taken before 27 weeks (n = 24) and 0.018 when taken at or after 27 weeks (n = 55). However, the slopes of the regression lines, with standardized hemoglobin as the outcome variable and standardized {Delta} OD 450 as the independent variable, did not differ significantly (P = .21) before and after 27 weeks’ pregnancy. In addition, in Figure 3Go, horizontal lines were drawn at the thresholds of Liley’s zones 1, 2c, and 3, and a vertical line at the threshold of severe anemia. As such, Figure 3Go can be read as a two-by-two table. Cases on the left of the vertical line were severely anemic, those above the chosen horizontal cutoff line (eg, zone 3 or zone 2c) were true-positives, and those below were false-negatives. Cases on the right of the vertical line were nonanemic or only moderately anemic, and those above the chosen cutoff were false-positives, whereas those below were true-negatives. Table 1Go lists the two-by-two tables and test characteristics of amniotic fluid {Delta} OD 450 in the prediction of severe anemia. Accuracy of the extrapolated Liley’s curve in predicting severe fetal anemia was 75% (95% CI 64, 84) for zone 3 and 86% (95% CI 77, 93) when the upper third of zone 2 was included. Sensitivity of Liley’s zone 3 was 74% (95% CI 49, 91) before and 81% (95% CI 67, 91) after 27 weeks. Sensitivity of Liley’s zone 3 including zone 2c was 95% (95% CI 74, 100) before and 98% (95% CI 89, 100) after 27 weeks.



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  		Figure 3. Relationship between standardized {Delta} OD 450 and standardized hemoglobin concentrations in 79 nonhydropic rhesus D-alloimmunized fetuses at the time of first blood sampling. Amniotic fluid {Delta} OD 450 was standardized by dividing the actual value by the value on the line between zones 1 and 2 for corresponding gestational age. Standardized hemoglobin concentrations were defined as the number of standard deviations that the actual value deviated from the normal mean for gestational age. The vertical broken line is drawn at the threshold of severe anemia (-5 standard deviations). Thus, this figure can be read as a two-by-two table: cases on the left of the vertical line were severely anemic, those above the chosen horizontal cutoff line (eg, zone 3 or zone 2c) were true-positives, and those below were false-negatives. Cases on the right of the vertical line were nonanemic or only moderately anemic, those above the chosen cutoff were false-positives, whereas those below were true-negatives.

Sikkel. Accuracy of {Delta} OD 450. Obstet Gynecol 2002.

 

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  		Table 1. Two-By-Two Tables and Test Characteristics of {Delta} OD 450 in the Prediction of Severe Anemia
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We compared {Delta} OD 450 with contemporaneous hemoglobin concentration in nonhydropic fetuses who were given their first intrauterine intravascular transfusion. The correlation between {Delta} OD 450 and fetal hemoglobin concentration in our study was weak. However, the clinical usefulness of {Delta} OD 450 was good because Liley’s zones 3 and 2c predicted severe anemia with an overall sensitivity of 79% and 97%, respectively. These sensitivities were roughly the same at gestational ages of 20–27 weeks and 27–35 weeks. Compared with previous studies on this subject,13–15,30 we used very stringent inclusion criteria and collected data on a relatively large number of patients. The data were prospectively collected in our clinical practice, and we adhered to current guidelines.5 We did not measure hemoglobin concentration in fetuses after 27 weeks with {Delta} OD 450 in Liley’s zone 2 unless repeated measurements showed a rising trend or ultrasound indicated a high risk of fetal anemia.

In 1986, Nicolaides et al published a paper with the challenging title "Have Liley Charts Outlived Their Usefulness?" in which they suggested that second-trimester {Delta} OD 450 values were unreliable in predicting severe anemia and that fetal blood sampling should replace amniocentesis.13 After excluding hydropic fetuses from that study, it appears that the upper half of Liley’s zone 2 had a 94% sensitivity and a 43% specificity in predicting fetal hemoglobin concentration less than 6 g/dL.13 In 1998, Rahman et al30 confirmed the results of the study by Nicolaides et al13 and also stated that predictions made on the basis of second-trimester {Delta} OD 450 measurements are inaccurate. They found an 80% sensitivity of Queenan’s zone 3 to predict a fetal hematocrit below 15%. Nevertheless, given the difference in procedure-related risk between amniocentesis and fetal blood sampling, we believe that sensitivities between 80% and 100%, as found by using the upper third of Liley’s zone 2, are acceptable. Therefore, we argue that {Delta} OD 450 measurements in the second and third trimester are still useful.

ACOG recommends diagnostic amniocentesis for alloimmunization with high antibody titers from as early as 20 weeks’ gestation and therapeutic intervention when {Delta} OD 450 is in Liley’s zone 3 or rising in the upper third of zone 2.5 The results of our study support this guideline: a 95% sensitivity for detecting severe fetal anemia was found. A specificity of 50% or less and the risk of repeated amniocentesis remain the major drawbacks of this approach. False-positive results of amniocentesis can lead to unnecessary intrauterine intravascular transfusions with procedure-related fetal loss rates of 1–3%.31 Fetal and perinatal procedure-related loss rates are reported to be 0.25–1% per amniocentesis.32,33 Another drawback of amniocentesis or fetal blood sampling is the risk of fetomaternal hemorrhage, which can increase the severity of alloimmunization. Fetomaternal hemorrhage occurs in 2.3% of cases after amniocentesis, and a significant increase in antibody titers occurs in 50% of cases after intrauterine intravascular transfusion.34,35 Thus, there is still a need for noninvasive tests that can predict fetal anemia with equal or higher accuracy.

Recent studies suggest that arterial and venous Doppler flow velocities in fetal vessels accurately predict anemia.22–25 These studies report that Doppler measurements have sensitivities between 63% and 100% and specificities between 70% and 100% in the prediction of severe fetal anemia when performed by experienced operators.22–25 However, there is a tendency to be overly optimistic about early results with new techniques. We are presently involved in a prospective multicenter trial to compare the diagnostic accuracy between {Delta} OD 450 measurements and maximum flow velocity in the fetal middle cerebral artery and the intrahepatic umbilical vein. Until the results of such prospective studies are available, we suggest that amniocentesis for {Delta} OD 450 measurement is still important in the management of severe rhesus D-alloimmunization.


   Footnotes
 
The authors thank Hans Egberts, PhD, Head of the Leiden University Medical Center Obstetrics Laboratory, for performing the {Delta} OD 450 measurements used in this study.

PII S0029-7844(02)01994-4

Received November 27, 2001. Received in revised form January 17, 2002. Accepted February 7, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Liley AW. Liquor amnii analysis in the management of the pregnancy complicated by rhesus sensitization. Am J Obstet Gynecol 1961;82:1359–70.[Medline]

2. Berkowitz RL, Hobbins JC. Intrauterine transfusion utilizing ultrasound. Obstet Gynecol 1981;57:33–6.[Abstract/Free Full Text]

3. Harman CR, Manning FA, Bowman JM, Lange IR. Severe Rh disease—poor outcome is not inevitable. Am J Obstet Gynecol 1983;145:823–9.[Medline]

4. Scott JR, Kochenour NK, Larkin RM, Scott MJ. Changes in the management of severely Rh-immunized patients. Am J Obstet Gynecol 1984;149:336–41.[Medline]

5. American College of Obstetricians and Gynecologists. Management of isoimmunization in pregnancy. ACOG technical bulletin no. 227. Washington, DC: American College of Obstetricians and Gynecologists, 1996.

6. Ananth U, Queenan JT. Does midtrimester delta OD450 of amniotic fluid reflect severity of Rh disease? Am J Obstet Gynecol 1989;161:47–9.[Medline]

7. Bock JE. Amniotic fluid bilirubin as a prognostic indicator in rhesus isoimmunization. Acta Obstet Gynecol Scand Suppl 1976;53(Suppl.):3–6.[Medline]

8. Fairweather DV, Whyley GA, Millar MD. Six years’ experience of the prediction of severity in rhesus haemolytic disease. Br J Obstet Gynaecol 1976;83:698–706.[Medline]

9. Pridmore BR, Robertson EG, Walker W. Liquor bilirubin levels and false prediction of severity in rhesus haemolytic disease. Br Med J 1972;3:136–9.

10. Queenan JT, Tomai TP, Ural SH, King JC. Deviation in amniotic fluid optical density at a wavelength of 450 nm in Rh-immunized pregnancies from 14 to 40 weeks’ gestation: A proposal for clinical management. Am J Obstet Gynecol 1993;168:1370–6.[Medline]

11. Robertson EG, Brown A, Ellis MI, Walker W. Intrauterine transfusion in the management of severe rhesus isoimmunization. Br J Obstet Gynaecol 1976;83:694–7.[Medline]

12. Whitfield CR. A three-year assessment of an action line method of timing intervention in rhesus isoimmunization. Am J Obstet Gynecol 1970;108:1239–44.[Medline]

13. Nicolaides KH, Rodeck CH, Mibashan RS, Kemp JR. Have Liley charts outlived their usefulness? Am J Obstet Gynecol 1986;155:90–4.[Medline]

14. Mackenzie IZ, Bowell PJ, Castle BM, Selinger M, Ferguson JF. Serial fetal blood sampling for the management of pregnancies complicated by severe rhesus (D) isoimmunization. Br J Obstet Gynaecol 1988;95:753–8.[Medline]

15. Scott F, Chan FY. Assessment of the clinical usefulness of the ‘Queenan’ chart versus the ‘Liley’ chart in predicting severity of rhesus iso-immunization. Prenat Diagn 1998; 18:1143–8.[Medline]

16. Weiner S, Bolognese RJ, Librizzi RJ. Ultrasound in the evaluation and management of the isoimmunized pregnancy. J Clin Ultrasound 1981;9:315–23.[Medline]

17. Vaughan JI, Warwick R, Letsky E, Nicolini U, Rodeck CH, Fisk NM. Erythropoietic suppression in fetal anemia because of Kell alloimmunization. Am J Obstet Gynecol 1994;171:247–52.[Medline]

18. Weiner CP, Widness JA. Decreased fetal erythropoiesis and hemolysis in Kell hemolytic anemia. Am J Obstet Gynecol 1996;174:547–51.[Medline]

19. Margulies M, Voto LS, Mathet E, Margulies M. High-dose intravenous IgG for the treatment of severe rhesus alloimmunization. Vox Sang 1991;61:181–9.[Medline]

20. Spinnato JA, Ralston KK, Greenwell ER, Marcell CA, Spinnato JA III. Amniotic fluid bilirubin and fetal hemolytic disease. Am J Obstet Gynecol 1991;165:1030–5.[Medline]

21. Oepkes D, Brand R, Vandenbussche FP, Meerman RH, Kanhai HH. The use of ultrasonography and Doppler in the prediction of fetal haemolytic anaemia: A multivariate analysis. Br J Obstet Gynaecol 1994;101:680–4.[Medline]

22. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9–14.[Abstract/Free Full Text]

23. Iskaros J, Kingdom J, Morrison JJ, Rodeck C. Prospective non-invasive monitoring of pregnancies complicated by red cell alloimmunization. Ultrasound Obstet Gynecol 1998;11:432–7.[Medline]

24. Oepkes D, Kanhai HH, Arabin B. Systematic antenatal functional evaluation in pregnancies at risk of progressive fetal anemia. In: Chervenak FA, Kurjak A, eds. Current perspectives on the fetus as a patient. New York: Parthenon Publishing Group, 1996;423–37.

25. Teixeira JM, Duncan K, Letsky E, Fisk NM. Middle cerebral artery peak systolic velocity in the prediction of fetal anemia. Ultrasound Obstet Gynecol 2000;15:205–8.[Medline]

26. Kanhai HH, Bennebroek Gravenhorst J, van Kamp IL, Meerman RH, Brand A, Dohmen-Feld MW, et al. Management of severe hemolytic disease with ultrasound-guided intravascular fetal transfusions. Vox Sang 1990;59: 180–4.[Medline]

27. Rodeck CH, Nicolaides KH, Warsof SL, Fysh WJ, Gamsu HR, Kemp JR. The management of severe rhesus isoimmunization by fetoscopic intravascular transfusions. Am J Obstet Gynecol 1984;150:769–74.[Medline]

28. Nicolaides KH, Soothill W, Clewell WH, Rodeck CH, Mibashan RS, Campbell S. Fetal haemoglobin measurement in the assessment of red cell isoimmunisation. Lancet 1988;i:1073–5.

29. van Kamp IL, Klumper FJ, Bakkum RS, Oepkes D, Meerman RH, Scherjon SA, et al. The severity of immune fetal hydrops is predictive of fetal outcome after intrauterine treatment. Am J Obstet Gynecol 2001;185:668–73.[Medline]

30. Rahman F, Detti L, Ozcan T, Khan R, Manohar S, Mari G. Can a single measurement of amniotic fluid delta optical density be safely used in the clinical management of Rhesus-alloimmunized pregnancies before 27 weeks’ gestation? Acta Obstet Gynecol Scand 1998;77:804–7.[Medline]

31. Klumper FJ, van Kamp IL, Vandenbussche FP, Meerman RH, Oepkes D, Scherjon SA, et al. Benefits and risks of fetal red-cell transfusion after 32 weeks’ gestation. Eur J Obstet Gynecol Reprod Biol 2000;92:91–6.[Medline]

32. Bowman JM. The management of Rh-Isoimmunization. Obstet Gynecol 1978;52:1–16.[Free Full Text]

33. Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-Pedersen B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;i:1287–93.

34. Bowman JM, Pollock JM. Transplacental fetal hemorrhage after amniocentesis. Obstet Gynecol 1985;66: 749–54.[Abstract/Free Full Text]

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