Anti-D quantification in relation to anti-D titre, middle cerebral artery Doppler measurement and clinical outcome in RhD-immunized pregnancies.

BACKGROUND: The optimal strategy to monitor RhD-immunized pregnancies is not evident. Whether a quantitative analysis of anti-D antibodies adds valuable information to anti-D titre is unclear. The aim of this study was to evaluate the relevance of anti-D quantification in routine monitoring of RhD-immunized pregnancies. MATERIALS AND METHODS: In a retrospective study, 64 consecutive pregnancies in 61 immunized women with anti-D titre ≥128 at any time during pregnancy were included. According to routine, at titre ≥128, anti-D quantification was performed by flow cytometry and the peak systolic velocity in the middle cerebral artery was measured by ultrasound. Decisions for treatment with intrauterine blood transfusion were based on increased peak systolic velocity in the middle cerebral artery. RESULTS: Increasing anti-D concentrations correlated well to increasing anti-D titres, but at each titre value, there was a large interindividual variation, in the determined anti-D concentration. Intrauterine transfusions were initiated in 35 pregnancies according to algorithms based on ultrasound measurements, at anti-D concentrations of 2·4-619 IU/ml and titre 128-16 000. Sixty pregnancies resulted in a live-born child, three in miscarriage and one in termination of pregnancy. During the perinatal care in the neonatal intensive care unit, thirty-one of the neonates were treated with blood exchange transfusions and/or red cell transfusions and 47 were treated with phototherapy. CONCLUSION: Anti-D quantification does not add further information compared to anti-D titre, in defining a critical level to start monitoring RhD-immunized pregnancies with Doppler ultrasound.

Fetal middle cerebral artery Doppler to time intrauterine transfusion in red-cell alloimmunization: a randomized trial.

OBJECTIVES: To evaluate whether Doppler measurement of middle cerebral artery peak systolic velocity (MCA-PSV) for timing subsequent intrauterine transfusions (IUTs) in fetuses that had undergone one IUT for anemia secondary to red-cell alloimmunization is non-inferior to timing based on expected decrease in fetal hematocrit (Hct) or fetal hemoglobin level, without compromising infant hemoglobin at birth. METHODS: This was an international, pragmatic multicenter randomized controlled trial. Women with a pregnancy complicated by fetal anemia secondary to red-cell alloimmunization (due to any antibody alone or in combination), as indicated by the need to undergo a single IUT, were eligible for inclusion. Women were randomized to the determination of timing of further transfusion(s) by Doppler measurement of MCA-PSV (MCA-PSV Group), with a serial upward trend of values >1.5 multiples of the median considered indicative of the need for another IUT, or timing of transfusion by a decrease in fetal Hct (fetal Hct Group), with subsequent IUTs timed according to an estimated fall in fetal Hct of 1% per day or fetal hemoglobin of 0.3 g/dL per day, to maintain fetal hemoglobin level between 7 and 10 g/dL. The primary outcome was infant hemoglobin level measured at birth. RESULTS: A total of 71 women were randomized, 36 to the MCA-PSV Group and 35 to the fetal Hct Group. Median gestational age at randomization was 30.3 weeks, the majority of women were Caucasian and non-smokers, 9.9% of women had Kell alloimmunization, and 14% of fetuses were hydropic at their first IUT. No statistically significant differences between the two treatment groups were observed with regard to mean hemoglobin levels at birth (MCA-PSV Group, 10.36 ± 3.82 g/dL vs fetal Hct Group, 12.03 ± 3.14 g/dL; adjusted mean difference -1.56 g/dL (95% CI, -3.24 to 0.13 g/dL); P = 0.070), or the number of IUTs performed after randomization (MCA-PSV Group, 1.75 ± 1.79 vs fetal Hct Group 1.80 ± 1.32; adjusted relative risk 0.88 (95% CI, 0.61-1.26); P = 0.474). There was no statistically significant difference between the two groups with respect to the risk of adverse infant outcomes related to alloimmunization or procedure-related complications. CONCLUSION: Both Doppler measurement of MCA-PSV and estimation of the decrease in fetal Hct or hemoglobin can be used to determine the timing of second and subsequent IUTs in fetuses with red-cell alloimmunization. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

[Anti-D isoimmunization severe in a twin pregnancy. Case report]. / Isoinmunización grave anti-D en una gestación gemelar. Caso clínico.

Perinatal hemolytic disease occurs secondary to a hemolytic phenomenon of immune origin resulting in fetal or neonatal anemia. A 38-year-old pregnant woman was referred to the Department of high risk Obstetrics, Hospital Universitario La Paz Madrid because of presenting a dichorionic diamniotic twin pregnancy spontaneously, pre-pregnancy diabetes poorly controlled and severe alloinmunization anti-D. Her first pregnancy ended in a normal delivery at term; in the period of 4 years, she has three newborn with 36, 34 and 40 weeks respectively, who die with a week of life. After that, two intrauterine fetal death occur at 26 weeks of gestation. The patient who is RhD negative, suffers anti-D inmunization with a antibody titration of 1/1024 with 14 weeks of gestation. Twelve plasmapheresis, eight doses of anti-D inmunoglobulins and intrauterine transfusions has been the treatment received. A severe anemia is found during the ultrasound control of the middLe cerebral artery peak systolic velocity in both twins since the 16th week. It remains stable thanks to the treatment. Finally at the 28th week of gestation, pregnancy is terminated with a cesarean section. The twins are born alive and premature, but with good general state. The measurement of the middle cerebral artery peak systolic velocity predicts moderate-severe fetal anemia cases, which are the most important in the clinical management because of the need of active treatment or finish the pregnancy.

[Use of peak systolic velocity in the middle cerebral artery after serial intravenous fetal exchange transfusions in the end of pregnancy]. / Intérêt du pic systolique de vélocité dans l'artère cérébrale moyenne en fin de grossesse après exsanguino-transfusions itératives.

OBJECTIVES: Our aim was to assess the efficiency of the peak systolic velocity in the middle cerebral artery (PSV-MCA) to predict neonatal anemia at the end of pregnancies after serial intravenous fetal exchange transfusions (IFET) for red-cell fetomaternal immunization. PATIENTS AND METHODS: We conducted a retrospective study from 01/01/2004 to 31/12/2009 of 25 pregnancies after IFET for red-cell fetomaternal immunization, in Saint Vincent de Paul Hospital, Paris. The study assessed correlation between the last prenatal PSV-MCA measured and hemoglobin concentration at birth and other neonatal data. RESULTS: Last prenatal PSV-MCA and hemoglobin concentration at birth were significantly correlated (r=-0.39, P<0.01). CONCLUSION: There is a good correlation between last PSV-MCA measured before birth and neonatal haemoglobin and complexity of neonatal care linked to anemia. Cerebral Doppler is useful for the follow-up of pregnancies at risk for anemia even in the end of the pregnancy and after serial intravenous fetal exchange transfusions.

Diagnostic laboratory technologies for the fetus and neonate with isoimmunization.

Maternal-fetal blood group incompatibility is common but less commonly results in hemolytic disease of the fetus and newborn (HDFN). HDFN is associated with greater peak bilirubin, at an earlier age, and for longer duration than other causes of hyperbilirubinemia. It poses a substantial risk for kernicterus and accounts for the majority of exchange transfusions for hyperbilirubinemia. Advances in diagnosis and management are described, from identification of the alloimmunized pregnancy by maternal ABO and Rh typing, antibody screen (indirect Coombs test), identification and titration; laboratory evaluation of the maternal-fetal unit with a critical maternal antibody titer to prompt fetal antigen status determination; assessment of fetomaternal hemorrhage by conventional Kleihauer-Betke testing or by flow cytometric methodology; to antenatal management of isoimmunization and fetal status assessments using the systems of Liley, Queenan, and serial Doppler fetal middle cerebral artery peak velocity measurements. The utility of laboratory diagnostics in the approach to hemolysis in the neonate, including hematology, chemistry, and peripheral blood smear review, is reviewed. The goal of management, to deliver a healthy infant at or near term, is attained for the majority of cases using current modalities; future directions include noninvasive genotyping of fetal blood from maternal serum to fully eliminate RhD alloimmunization and HDFN; and development of prophylaxis and intervention strategies for non-RhD alloimmunizations for which immune globulin is currently unavailable.

The MCA Doppler and its role in the evaluation of fetal anemia and fetal growth restriction.

Doppler velocimetry of the middle cerebral artery (MCA) has played a major role in fetal medicine for the last 23 years, both in intrauterine growth-restricted (IUGR) and anemic fetuses. Its utility in the diagnosis and management of cases of fetal anemia was initially demonstrated in cases of red cell alloimmunization and later extended to other types of anemia. In addition, MCA Doppler studies are crucial in the evaluation of IUGR fetuses. This article is a review of the role of the MCA in these 2 conditions.

Successful management of anti-Jra alloimmunization in pregnancy: a case report.

BACKGROUND: Hemolytic disease of the fetus/newborn due to Jr(a) immunization is very rare and considered to be mild, and only routine obstetrical care is recommended for pregnant women sensitized to the Jr(a) antigen. CASE REPORT: A 20-year-old nulliparous woman was referred to our hospital for perinatal management. Her indirect Coombs test was positive for anti-Jr(a) antibody (1:64). At 33 weeks' gestational age, we observed that fetal growth was mildly restricted and the peak systolic velocity of the fetal middle cerebral artery (PSV-MCA) was above the upper limit of the reference range (1.55 multiples of the median). Amniocentesis was also carried out and the DeltaOD450 value was in the lower mid-zone of the Liley curve. We continued to carefully observe the patient because we observed PSV-MCA values within 1.50-1.60 multiples of the median and no other findings of fetal anemia. She vaginally delivered a female infant weighing 2,136 g at 37 weeks' gestational age. The infant received treatment with both iron and recombinant erythropoietin without developing hyperbilirubinemia and blood transfusion. CONCLUSION: PSV-MCA should be monitored for the detection of fetal anemia, even in pregnant women sensitized to some antigens for which only routine obstetrical care is recommended.

Fetal transfusion of red blood cells for alloimmunization: validity of a published equation.

OBJECTIVE: To validate the equation published in 1990 by Leduc et al. for red blood cell fetal transfusion where fetoplacental blood volume (VO) = 100 ml/kg, then improve its precision. METHODS: We reviewed 101 fetal transfusions among 32 patients. We analyzed risk factors for an inaccurate estimation with uni- and multivariate analysis. We compared the obtained Leduc formula with three other published equations. RESULTS: Fetal weight and gestational age were risk factors for an inaccurate estimation of the final Hct. Before 32 weeks the estimation of VO was 120 ml/kg instead of 100 ml/kg. All formulae overestimated the mean expected Hct value. However, expected Hct estimated by Leduc's formula is the nearest of the observed final Hct. CONCLUSION: Leduc's equation seems to be accurate, but less so for the youngest fetuses. We propose an adapted formula VO according to gestational age and fetal weight estimation.

Management of red cell alloimmunized pregnancies using conventional methods compared with that of middle cerebral artery peak systolic velocity.

The aim of this retrospective study was to find out the effect of change in the management of red cell alloimmunized pregnancies from conventional method of amniocentesis to the Doppler assessment of middle cerebral artery peak systolic velocity (MCA-PSV). There were 29 alloimmunized pregnancies affected by red cell antibodies. Ten cases were managed by amniocentesis and another 19 were managed by MCA-PSV measurements. The antenatal management and perinatal outcome of both groups are presented. This study suggests that the non-invasive monitoring should be the method of choice to monitor alloimmunized pregnancies.

Prenatal diagnosis of anoxic cerebral lesions caused by profound fetal anemia secondary to maternal red blood cell alloimmunization.

BACKGROUND: The long-term neurological prognosis of severe fetal anemia is usually considered favorable, especially when fetal hydrops regresses after successful in utero transfusion. CASES: We report two cases of prenatally diagnosed fetal cerebral anoxic lesions associated with severe fetal anemia despite appropriate and successful treatment by in utero transfusion. The two pregnancies were terminated. CONCLUSION: Profound fetal anemia may cause anoxic lesions of the fetal brain that may be diagnosed prenatally. If new onset ventriculomegaly is observed on ultrasonography after in utero transfusion for severe fetal anemia, anoxic lesions could be suspected.

Fetal middle cerebral artery Doppler velocimetry in cases of rhesus alloimmunization.

OBJECTIVE: To assess fetal middle cerebral artery (MCA) peak systolic velocity (PSV) in cases of rhesus alloimmunization and to establish whether MCA-PSV is valid for the prediction of fetal anemia. METHODS: The study population included 157 pregnant women diagnosed with rhesus alloimmunization. MCA-PSV measurements were obtained within 3 days of blood sampling for estimation of hemoglobin concentration either at delivery or cordocentesis by the same operator and by means of the same ultrasound machine using techniques described previously. To evaluate the measurements of the MCA-PSV as the multiples of median (MoM) for gestation we used original nomograms for various gestational ages derived from a group of 273 normal fetuses between 22 and 40 weeks of gestation, not at risk for anemia. Receiver-operator characteristic (ROC) curves were employed to evaluate the relation of the sensitivity (the true positive rate) and the false positive rate (100% specificity) of different threshold values of the MCA-PSV. RESULTS: The sensitivity of the MCA-PSV was 94.4% in the case of the subgroup of fetuses with severe anemia. The sensitivity of the MCA-PSV test decreased in less anemic fetuses and was 77.3% in the subgroup with moderate anemia and 32% in the subgroup with mild anemia. According to ROC curves, we selected the optimal MCA-PSV threshold values of 1.15, 1.44, and 1.53 MoM for the prediction of mild, moderate, and severe anemia, respectively. CONCLUSIONS: MCA-PSV is a significant Doppler index valid for the prediction of moderate and severe fetal anemia.

Increasing the noninvasive management of rhesus isoimmunization.

OBJECTIVE: To determine the clinical outcome of isoimmunized pregnancies managed by middle cerebral artery peak systolic velocity (MCA-PSV) in an intention-to-treat study. METHOD: Rhesus isoimmunized pregnancies were managed with serial ultrasound and Doppler studies at 7-day intervals up to 34 weeks of gestation, between 2001 and 2005. Invasive diagnostic and therapeutic procedures were carried out when MCA-PSV was indicative of moderate or severe anemia. RESULTS: The overall sensitivity in detecting moderate to severe fetal anemia at less than 34 weeks was 100% (95% confidence interval, 54.1-100.0 L). Twenty-two cases were managed with MCA-PSV. Twelve cases needed fetal blood sampling and 6 cases needed intrauterine transfusion. Cordocentesis revealed a hematocrit of more than 26% in 6 fetuses. CONCLUSION: Management by MCA-PSV Doppler at weekly intervals is a highly sensitive method for detecting fetal anemia. It reduces the number of fetal blood samples needed and significantly lowers interventional procedures.

[Use of peak systolic velocity of the middle cerebral artery in the management of fetal anemia due to fetomaternal erythrocyte alloimmunization]. / Intérêt pratique du pic systolique de vélocité à l'artère cérébrale moyenne dans la prise en charge des anémies foetales par allo-immunisation érythrocytaire.

OBJECTIVE: To assess the peak systolic velocity in the middle cerebral artery (PSV-MCA) in the prediction of fetal anemia in case of severe red-cell alloimmunization. METHODS: A prospective study, from January 2003 to April 2006, of 47 consecutive pregnancies with severe alloimmunization. Fetal surveillance was based on titration and dosage of antibodies, ultrasound scans, and doppler for PSV-MCA measurement up to twice a week. A fetal blood sampling and in utero transfusion was performed in case of increase in PSV-MCA above 1.5 multiples of the median (MoM), and/or signs of hydrops on ultrasound. Severe fetal anemia was defined by fetal hemoglobin below 0.55MoM for gestational age. Analyses performed included the correlation between PSV-MCA and fetal hemoglobin, the value of PSV-MCA in the prediction of severe fetal anemia, and the determination of adequate threshold for intervention based on ROC curve analysis. RESULTS: Four hundred and eighty-five PSV-MCA were performed in 47 high-risk pregnancies, of which 125 were coupled with hemoglobin measurement by fetal blood sampling. There is a significant negative correlation between PSV-MCA and fetal hemoglobin (R2=0.6545 ; p<0.0001). Based on all prospective data, the negative predictive value of PSV-MCA was 97.8 %, sensitivity was 86.7 %, with a false positive rate of 12.2%. Area under the ROC curve was 0.85 (IC 95 %, 0.742-0.927 ; p<0.0001), suggesting an excellent value of this test. When switching the threshold for intervention from 1.5 to 1.6MoM, the positive predictive value increased, without decrease in sensitivity or negative predictive value. CONCLUSION: This study confirms the correlation between PSV-MCA and fetal hemoglobin. It allows a decrease of invasive procedures in the follow-up of pregnancies with severe red-cell alloimmunization.

Cardiofemoral index as an ultrasound marker of fetal anemia in isoimmunized pregnancy.

OBJECTIVE: To test a new noninvasive ultrasound method for diagnosing fetal anemia in red blood cell isoimmunized pregnancies. METHODS: A diagnostic accuracy study was carried out to determine the cutoff point of an ultrasound measurement, the cardiofemoral index (CFI), calculated using the biventricular outer dimension (BVOD) and femur length to diagnosis severe anemia. The CFI measurement was performed before each of the 336 cordocenteses on 131 fetuses. Diagnosis test analysis and receiver-operating characteristics (ROC) curves were used and the area under the curve (AUC) was calculated to compare the overall accuracy of the CFI for anemia diagnosis, between fetuses with or without previous intrauterine transfusions (IUT). RESULTS: At first cordocentesis (n=131) the AUC was 0.75 (95% CI, 0.66-0.84). For cases where fetuses had undergone 1 previous transfusion (n=88) the AUC was 0.76 (95% CI, 0.64-0.88) and at the time of the third cordocentesis for IUT (n=53) it was 0.73 (95% CI, 0.59-0.86). For a 0.59 CFI threshold to diagnosis fetuses with hemoglobin deficit above 5 g/dL, sensitivity values were 87.2%, 88.0%, and 94.1% respectively for fetuses without IUT, with 1 IUT, and with 2 IUTs. Likelihood ratios for positive (LR+) and negative (LR-) test results were 1.98, 2.05, 1.69 and 0.23, 0.21, 0.13 respectively. CONCLUSION: The cardiofemoral index may be an effective noninvasive marker of severe fetal anemia in high-risk fetuses, with accuracy similar for fetuses either with or without previous transfusions.

Discordant middle cerebral artery peak systolic velocity Doppler studies in a fetus with RhD alloimmunization.

BACKGROUND: Doppler measurement of the fetal middle cerebral artery peak systolic velocity is a valuable tool in detecting the presence of fetal anemia in Rh-sensitized pregnancies. We present a case in which discordant left and right middle cerebral artery Dopplers complicated clinical management. CASE: An RhD-alloimmunized patient had middle cerebral artery Dopplers at 30 weeks of gestation, which showed an elevated peak systolic velocity in the left middle cerebral artery, greater than 1.55 multiples of the mean, but the right middle cerebral artery was within the normal range. The amniotic fluid change in optical density at a wavelength of 450 nm was consistent with the right middle cerebral artery Doppler. When both Dopplers were greater than or equal to 1.5 multiples of the mean, fetal blood sampling revealed a hematocrit of 28%. Postnatal cranial ultrasound examination showed normal architecture, but there was persistent discordant Dopplers in the left versus the right middle cerebral artery. CONCLUSION: Measurement of both left and right middle cerebral artery peak systolic velocities may identify patients with intrinsic variations in cranial blood vessels resulting in abnormal Doppler flows.

Correlation between middle cerebral artery peak systolic velocity and fetal hemoglobin after 2 previous intrauterine transfusions.

OBJECTIVE: The middle cerebral artery peak systolic velocity (MCA-PSV) has been successfully used for timing the first 2 transfusions in fetuses at risk for anemia because of maternal red cell alloimmunization. The objective of this study was to assess whether the correlation between the MCA-PSV and fetal hemoglobin is maintained in fetuses that had undergone 2 previous intrauterine transfusions. STUDY DESIGN: Doppler measurement of MCA-PSV was performed before cordocentesis in 39 fetuses. The timing of the third transfusion was based on traditional criteria. The values of MCA-PSV and hemoglobin were expressed as multiples of the median (MoM). Anemia was defined as mild (hemoglobin <0.84 MoM for a given gestational age, moderate (hemoglobin <0.65 MoM), and severe (hemoglobin <0.55 MoM). Regression analysis was used to assess the correlation between the MCA-PSV MoM and fetal hemoglobin MoM. RESULTS: Gestational age at Doppler study ranged from 22 to 35 weeks. Six fetuses (15%) had normal hemoglobin concentration; 21 (53%) had mild anemia; 7 (20%) had moderate anemia; and 5 (12%) had severe anemia. There was a linear correlation between fetal hemoglobin (y) and the MCA-PSV (x): y = 1.185 - 0.341x. CONCLUSION: Previously, concerns have been expressed about the accuracy of Doppler prediction of anemia after previous transfusions. Our data suggest that there is a good correlation between the MCA-PSV and fetal hemoglobin in fetuses that have undergone 2 previous transfusions. Our findings expand the clinical situation in which Doppler can be used to monitor red cell alloimmunized pregnancies.

Reassuring fetal middle cerebral artery doppler velocimetry in alloimmunised pregnancies: neonatal outcomes without invasive procedures.

OBJECTIVE: To assess the neonatal outcome in red blood cell alloimmunised pregnancies at increased risk of fetal anaemia where invasive testing was avoided based on reassuring middle cerebral artery (MCA) Doppler velocity results. METHODS: We included 28 alloimmunised pregnant women at significant risk of fetal or neonatal anaemia who did not have invasive testing because of reassuring MCA Doppler velocimetry. Women requiring invasive testing or intrauterine transfusion were excluded. Outcome measures were admission to neonatal intensive care unit, cord haemoglobin and bilirubin levels and neonatal therapy. RESULTS: Ten neonates (36%) were anaemic at birth while 18 (64%) had normal haemoglobin. Seven neonates (25%) did not require any form of neonatal therapy, 10 (36%) had phototherapy only, 7 (25%) required exchange transfusions and 4 (14%) top-up transfusions. There were no treatment-related complications. Mean cord haemoglobin was 13.9 g/dl (range 7-18.9) and mean bilirubin was 84.1 micromol/l (range 29-192). CONCLUSION: Avoiding invasive procedures in pregnancies at risk of fetal anaemia by relying on reassuring MCA Doppler velocimetry did not result in life-threatening fetal or neonatal morbidities. The extent of neonatal therapy was acceptable. The routine use of this test can lead to less unnecessary invasive procedures in at-risk fetuses.

Prediction of fetal anemia in pregnancies with red-cell alloimmunization: comparison of middle cerebral artery peak systolic velocity and amniotic fluid OD450.

OBJECTIVE: To compare the accuracy of Doppler velocimetry (middle cerebral artery peak systolic velocity, MCA-PSV) and amniocentesis (amniotic fluid delta optical density 450 (OD450)) for the detection of fetal anemia against the gold standard of fetal blood sampling (FBS). METHODS: Thirty-eight pregnancies were identified to be at risk of fetal anemia from immune causes between January 2000 and May 2002. In a cross-sectional diagnostic accuracy study, MCA-PSV and amniotic fluid delta OD450 values were plotted on reference charts and compared to an FBS obtained within the subsequent 7 days. Receiver-operating characteristics (ROC) curves were used and the area under the curve (AUC) calculated to compare the overall accuracy of the two tests. Sensitivity, specificity and likelihood ratios for positive (LR+) and negative (LR-) test results were generated for specific thresholds of MCA-PSV and delta OD450. RESULTS: For MCA-PSV (n = 38), the AUC was 0.71 (95% CI 0.57-0.85) and for amniotic fluid delta OD450 (n = 22) it was 0.68 (95% CI 0.49-0.87) compared with FBS within 7 days. Sensitivity, specificity and LR+, LR- for MCA-PSV were 64%, 81%, 3.4 and 0.5, respectively, and 53%, 71%, 1.9 and 0.7 for amniotic fluid OD450, respectively. CONCLUSION: MCA-PSV and OD450 have similar test accuracy in detecting fetal anemia. MCA-PSV is non-invasive and therefore presents no risk of miscarriage or preterm labor and thus is a preferable method of screening for fetal anemia.