A family affair-Severe fetal and neonatal hemolytic anemia due to novel alpha-spectrin mutations in two siblings.

Hereditary spherocytosis (HS) is the most common cause of inherited, nonimmune hemolytic anemia. When inherited in an autosomal dominant fashion, the anemia is typically mild. However, severe, transfusion-dependent anemia is seen in autosomal recessive HS, which is often associated with deficient or absent red blood cell membrane protein alpha-spectrin. We report a 26-year-old para one who was referred to our center at 28 weeks' gestation due to concerns for fetal anemia. Evaluation revealed elevated peak systolic velocity in the middle cerebral artery by Doppler scan and fetal cardiomegaly. Fetal hematocrit obtained by sampling the umbilical vein was 9% confirming severe fetal anemia. Fetal peripheral smear was consistent with hereditary spherocytosis. Genetic analysis of both parents confirmed heterozygosity for the SPTA1 variants (pathogenic variant c.4180del (p.C1394Afs*25), and a variant of uncertain significance, c.1677G>T (p.G449G)) detected by a hemolytic anemia panel in the patient's first child. It is important to consider genetic causes of anemia in patients presenting with severe nonimmune fetal anemia, including autosomal recessive HS. We present a case of autosomal recessive HS with a novel pathogenic variant in the SPTA1 gene which resulted in significant impact on prenatal management.

MRI Patterns of brain injury and neurodevelopmental outcomes in neonates with severe anaemia at birth.

AIMS: To define patterns of brain injury and associated neurodevelopmental outcomes in infants with severe neonatal anaemia. METHODS: We studied 20 infants with severe anaemia at birth (haemoglobin<7g/dL). Clinical details were analysed for causes of anaemia and co-morbidities. All had early brain magnetic resonance imaging (MRI) scans, which were reviewed for injury pattern. Neurodevelopmental outcomes were assessed at a median age of 24months. RESULTS: The aetiology of the anaemia was feto-maternal haemorrhage in 17 and antepartum haemorrhage in 3 infants. The predominant site of injury was the white matter, which was affected in all infants, with differing grades of severity and with cystic evolution in 45%. Only one infant showed an injury pattern typical of an acute severe hypoxic-ischaemic insult. Outcomes correlated closely to the severity of MRI findings. Cerebral palsy was seen only with the most severe neuroimaging patterns (n=6). Global developmental delay, learning or behavioural problems and seizures were common with moderate injury. Visual impairment occurred, particularly with posterior injury. Microcephaly developed in 45%. INTERPRETATION: Severe neonatal anaemia at birth was associated with a white matter predominant pattern of injury, the severity of which was related to neurodevelopmental outcomes. Early MRI and long-term follow-up are advisable following severe neonatal anaemia.

Ventricular Diastolic Function in Normal Fetuses and Fetuses with Hb Bart's Disease Assessed by Color M-Mode Propagation Velocity using Cardio-STIC-M (Spatio-Temporal Image Correlation M-Mode).

Purpose: To determine whether ventricular diastolic dysfunction contributes to the pathogenesis of fetal cardiac failure due to fetal anemia using fetal Hb Bart's disease as a live model and cardio-STIC-M as a diagnostic tool. Materials and Methods: Color cardio-STIC volume datasets were acquired from fetuses at risk for Hb Bart's disease during 18 - 22 weeks of gestation and normal pregnancies and pregnancies with hydrops fetalis caused by Hb Bart's disease at 28 - 32 weeks. The volumes were analyzed off-line for velocity propagation (Vp) of the right and left ventricles to assess ventricular diastolic function using color cardio-STIC-M. Results: The Vp for the right and left ventricles was studied in fetuses at 18 - 22 weeks, including 64 normal fetuses (group 1) and 22 fetuses with Hb Bart's disease (group 2), and in fetuses at 28 - 32 weeks, including 22 normal fetuses (group 3) and 16 fetuses with Hb Bart's hydrops fetalis (group 4). The Vp of the fetuses in group 1 and group 2 was not significantly different. However, the Vp for the right and left ventricles in group 4 was significantly lower than in group 3 (19.02 vs. 9.78, p < 0.001; and 20.24 vs. 13.40, p < 0.001, respectively). The inter-observer variability had fair agreement with the intra-class correlation coefficient of 0.531 (95 % CI 0.393 - 0.646, p < 0.001). Conclusion: Hydrops fetalis secondary to fetal anemia is initially caused by hypervolemia rather than ventricular diastolic dysfunction while ventricular diastolic compromise is a late occurring consequence of persistent hypervolemia, different from the mechanism of hydropic changes caused by cardiac causes.

[THE FETAL MIDDLE CEREBRAL ARTERY PEAK SYSTOLIC VELOCITY AS A PEDICTOR OF FETAL ANEMIA IN RH-ALLOIMMUNIZED PREGNANCY].

UNLABELLED: Rh-isoimmunization is a pathological condition in which the fetal red blood cells of a Rh (+) fetus are destroyed by the isoantibodies of a Rh (-) woman sensitized in a previous event. Despite of the wide spread implementation of anti D-gammaglobolin prophylaxis this is still the most common cause for fetal anemia. Recently, sonographic measurement of the fetal middle cerebral artery peak systolic velocity (MCA-PSV) has been shown to be an accurate non-invasive test to predict low fetal hemoglobin levels. We present a case report of Rh-alloimmunized pregnancy with moderate fetal anemia, followed-up by weekly MCA-PSV measurements. CASE REPORT: A 37-year-old Rh (-) negative gravida 3, para 1, without anti-D gammaglobolin prophylaxis in her previous pregnancies, presented at 27+0 weeks of gestation (w.g.) for a routine third trimester scan. Subsequent ultrasound measurements of MCA-PSV confirmed a progressive increase of the peak systolic velocities from 40 to 80 cm/sec, as well as a gradual rise in the anti-D titers. The evidence of developing fetal anemia necessitated elective Caesarean section performed at 35 wg. The neonate was admitted in the intensive care unit and required resuscitation, one exchange blood transfusion and several courses of phototherapy. The patient was discharged two weeks post partum. CONCLUSIONS: There is a strong correlation between the high peak systolic velocities in the middle cerebral artery (MCA-PSV) and the low levels of fetal hemoglobin. The high sensitivity and positive predictive value concerning the development of fetal anemia, as well as its good repeatability, makes this non-invasive test a valuable asset in the management of all pregnancies complicated by severe Rh-alloimmunization.

Evaluation of prenatal and postnatal diagnostic criteria for twin anemia-polycythemia sequence.

OBJECTIVE: The aim of this study is to analyze the relevance of the prenatal and postnatal diagnostic parameters of twin anemia-polycythemia sequence (TAPS). METHODS: Diagnostic data of all cases of TAPS followed in our institution between 2006 and 2013 were reviewed. Statistical analyses were conducted using Bayesian methods. RESULTS: Twenty cases of TAPS were included. We found a relationship between the hemoglobin level and the middle cerebral artery peak systolic velocity (coefficient -0.25 [-0.34, -0.15], Pr(coef < 0) = 99.99%). Sensitivity and specificity of the prenatal diagnosis were 71% and 50%, respectively, regarding the correspondence with postnatal diagnosis. There was no correlation between the number [odds ratio (OR) = 0.89 [0.72, 1.10], Pr(OR > 1) = 14.8%)], the mean diameter (OR = 0.98 [0.32, 3.06], Pr(OR > 1) = 48.9%), or the total diameter (OR = 0.79 [0.36, 1.53], Pr(OR > 1) = 26.3%) of arteriovenous anastomoses and the severity of TAPS. CONCLUSION: Middle cerebral artery peak systolic velocity is a reliable tool for estimating the hemoglobin level in cases of TAPS. The correspondence between prenatal and postnatal diagnosis is imperfect. Further studies are required to evaluate opportunity of widening postnatal diagnostic criteria. © 2014 John Wiley & Sons, Ltd.

Myocardial assessment using tissue doppler imaging in preterm very low-birth weight infants before and after red blood cell transfusion.

OBJECTIVE: To investigate myocardial velocities in anemic very low-birth weight (VLBW) preterm infants, pre and post red blood cells transfusion using tissue Doppler imaging echocardiography. STUDY DESIGN: Forty-eight VLBW preterm infants34 weeks and>2 weeks old were prospectively divided: Transfused symptomatic infants (Hematocrit (Hct)<0.30 (n=32)) and non transfused asymptomatic controls (control 1, Hct >0.30 (n=9) and control 2, Hct <0.30 (n=7)). Echocardiography was performed before and 3-5 days after transfusion in the transfused, and the controls were studied at similar intervals. Non parametric tests were used for statistical analysis. RESULT: Left ventricular (LV) systolic velocity increased (transfused (4.6±0.70 vs 6.0±0.65, P<0.01)) as did LV diastolic velocities (P<0.01) without significant difference over time in each control. The percentage change in LV velocity following transfusion correlated negatively (ρ=0.36) with pre transfusion Hct. CONCLUSION: There is a significant increase in myocardial performance following transfusion, which is related to the severity of the anemia.

Doppler middle cerebral artery peak systolic velocity for diagnosis of neonatal anemia.

OBJECTIVES: The peak systolic velocity (PSV) of the middle cerebral artery was found to be predictive of fetal anemia and is routinely applied in the treatment of such fetuses. Our objective was to determine whether a correlation exists between the PSV in the neonatal middle cerebral artery and hemoglobin levels for possible future implementation in clinical practice. METHODS: A prospective study on 151 neonates was conducted, examining their middle cerebral artery PSV concomitantly with their hemoglobin level during the first 36 hours after delivery. The study population included 122 normocythemic, 24 anemic, and 5 polycythemic neonates. An analysis of variance between normocythemic, anemic, and polycythemic neonates was performed, and a regression analysis of the PSV versus hemoglobin levels was conducted. RESULTS: The normocythemic neonates had a mean middle cerebral artery PSV ± SD of 41.3 ± 11.4 cm/s, whereas the anemic neonates had a significantly higher PSV (63.8 ± 28.5 cm/s), and the polycythemic neonates had a significantly lower PSV (26.8 ± 7.4 cm/s; P < .001). A statistically significant correlation was found between hemoglobin levels and the middle cerebral artery PSV (P < .01). CONCLUSIONS: Neonatal anemia and polycythemia can be rapidly diagnosed at the bedside by examining the middle cerebral artery PSV. This technique can be used as an ancillary measure to promptly diagnose acute neonatal blood volume changes for an immediate intervention.

Fetal and neonatal anemia associated with anti-Jr(a) : a case report showing a poorly hemolytic mechanism.

Although recently published case reports suggest the significance of Jr(a) alloimmunization in the obstetric setting, the involved mechanism still remains unclear. Here we report a case of severe fetal and neonatal anemia associated with anti-Jr(a) alloimmunization, which was successfully managed using Doppler assessment of peak systolic velocity of the fetal middle cerebral artery (MCA-PSV). A Japanese woman with anti-Jr(a) (titer 1024) was referred to our department at 20 weeks' gestation. As fetal MCA-PSV exceeded 1.5 multiple of median, labor was induced and a female neonate of 1998 g was delivered vaginally at 33 weeks and 5 days of gestation. The infant's hematocrit and hemoglobin levels were 25.4% and 82 g/L, respectively, but her total bilirubin level (15 µmol/L; 0.9 mg/dL) and reticulocyte counts (4.5%) were low. During the course, the infant showed no apparent signs of hemolysis. Jr(a) alloimmunization should be recognized as a possible cause of fetal anemia with no direct hemolytic process.

Middle cerebral artery-peak systolic velocity in dizygotic twins with anti-E alloimmunization.

Middle cerebral artery-peak systolic velocity (MCA-PSV) has been reported to predict fetal anemia with similar accuracy as amniotic ΔOD450 assay. Alloimmunized dizygotic twin pregnancy allows us to compare anemic and non-anemic twins in the same intrauterine environment. We herein present a case of Rh (E)-incompatible dizygotic twin pregnancy, where MCA-PSV could precisely detect the anemia in one of the twins. A 36-year-old woman, whose previous child required exchange transfusion due to hemolytic anemia of newborn (HFDN), conceived twins after in vitro fertilization-embryo transfer. At 24 weeks' gestation, MCA-PSV of twin A and twin B were 23.9 cm/s (0.8 multiples of median; MoM) and 30.7 cm/s (1.0 MoM), respectively. At 31 weeks' gestation, MCA-PSV values of both twins were sharply elevated to nearly 1.4 MoM. Thereafter, MCA-PSV of twin A fell to 1.0 MoM, whereas MCA-PSV of twin B exceeded 1.5 MoM at 34 weeks' gestation. Development of fetal anemia was suspected and emergency cesarean section was performed. Twin B showed moderate anemia with positive direct Coombs' test and was diagnosed as HFDN due to anti-E alloimmunization. Twin B required phototherapy and red cell transfusion, but exchange transfusion was safely obviated.

Combined use of the cardiofemoral index and middle cerebral artery Doppler velocimetry for the prediction of fetal anemia.

OBJECTIVE: To assess the accuracy of the combined use of the cardiofemoral index (CFI) and the middle cerebral artery peak systolic velocity (MCA-PSV), converted to multiples of the median (MoM), as noninvasive means to detect severe fetal anemia. METHOD: We measured CFI and MCA-PSV MoM in 37 fetuses just before their first (n=37), second (n=22), and third (n=14) cordocenteses and transfusions. Then, using 2 different criteria for severe fetal anemia detection (Hb deficit ≥7 g/dL and hemoglobin level ≤0.55 of MoM), we assessed their hemoglobin status during cordocentesis and the accuracy of CFI and MCA-PVS was determined. RESULTS: At the first cordocentesis the mean hemoglobin level was 8.5±3.6 g/dL and 15 fetuses (40.5%) had hydrops. In a total of 81 fetal evaluations, 58 (71.6%) of the CFIs and 34 (42.0%) of the MCA-PSV MoM measurements were abnormal. The result of one of these tests was abnormal in 65 evaluations (80.3%) and the results of both tests were abnormal in 27 evaluations (33.3%). All fetuses diagnosed as being severely anemic by at least one of the hemoglobin criteria during cordocentesis had an abnormal result by at least one of the noninvasive tests. Before the second and third transfusions, the combined use of the CFI and MCA-PSV MoM predicted severe fetal anemia with 100% sensitivity. When the CFI and MCA-PSV MoM measurements were normal, the negative likelihood ratio was zero. CONCLUSION: When associated, CFI and MCA-PSV MoM were accurate predictors of severe fetal anemia.

Twin anemia polycythemia sequence from a prenatal perspective.

OBJECTIVES: To describe the prevalence, management and outcome of spontaneous twin anemia polycythemia sequence (TAPS) diagnosed in the prenatal period. METHOD: Retrospective analysis of 142 consecutive monochorionic twin pregnancies not diagnosed with twin to twin transfusion syndrome. TAPS cases were identified based on the presence of discordant middle cerebral artery peak systolic velocity (MCA-PSV) measurements and signs suggestive of a chronic intertwin transfusion imbalance: either an elevated reticulocyte count in the anemic twin or the presence of few small unidirectional anastomoses during fetoscopy or at postnatal placental examination. RESULTS: Three cases were identified, giving an estimated prevalence of 2%. Prenatal interventions were tailored to the characteristics of each case and consisted of intrauterine transfusion and interruption of the shared circulation by cord coagulation or laser separation. CONCLUSION: In monochorionic twin pregnancies, TAPS is an uncommon prenatal finding. Nonetheless, its incidence seems high enough to recommend screening for this disease by MCA-PSV measurements.

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.

[Chemotherapy-induced fetal anemia in maternal acute myelocytic leukemia]. / Chemotherapieinduzierte fetale Anämie bei akuter myeloischer Leukämie der Mutter.

This article discusses the management of a pregnancy of a 32-year-old primigravida with acute myelocytic leukemia treated with induction chemotherapy starting in the 20 + 5 week of gestation. Sonographic monitoring showed evidence of fetal ascites and anemia that could be treated with an intrauterine fetal transfusion. After maternal recovery, a caesarean section was performed in the 27 + 5 week of gestation. We delivered a vivid eutrophic female prematurely. The infant showed persisting signs of myelosuppression. Two further transfusions had to be performed. The present report describes the interdisciplinary therapeutic management when polychemotherapy during pregnancy is necessary for the mother. Cases of acute leukemia in pregnancy are complicated by severe prenatal risks caused by the hematologic illness and by the immediate beginning of chemotherapy. In the third trimester premature delivery is preferable to intrauterine exposition to cytostatic agents. In the second trimester the pregnancy has to be monitored for the typical risks and complications of chemotherapy. Fetal cytotoxic myelosuppression is detectable by prenatal observation so that interventional strategies are feasible.

Management of Kell isoimmunization--evaluation of a Doppler-guided approach.

OBJECTIVE: To assess the role of peak systolic velocity in the middle cerebral artery (MCA-PSV) in the management of pregnancies complicated by Kell isoimmunization. METHODS: Sixteen fetuses were monitored by conventional protocol (Group 1) and eight fetuses by an MCA-PSV-guided protocol (Group 2). The conventional protocol included a weekly ultrasound evaluation and measurement of maternal anti-Kell titers every 4-6 weeks. In Group 2 Doppler assessment of the MCA-PSV was performed at intervals of 4 to 7 days and MCA-PSV>1.5 multiples of the median (MoM) was considered as an indication for fetal blood sampling (FBS). RESULTS: No parameter emerged as a reliable predictor of isoimmunization severity in Group 1. In Group 2, no FBS was necessary in one case since the MCA-PSV values obtained during the follow-up were <1.29 MoM. In two cases the first FBS was already indicated after 1 week of follow-up, but five other fetuses were followed for 3-9 weeks before FBS was indicated. All fetuses with MCA-PSV>1.5 MoM prior to intrauterine transfusion (IUT) had severe fetal anemia on FBS. In fetuses with severe anemia on the first FBS, the MCA-PSV values 7 days before the first FBS were <1.29 MoM (four cases), between 1.29 and 1.5 MoM (two cases) and >1.55 MoM (one case). CONCLUSIONS: In the management of Kell isoimmunization invasive procedures may be avoided by implementing MCA-PSV measurements. Delineation of appropriate intervals between reassessments, the reliability of MCA-PSV following repeated IUTs, and cut-off values for FBS await further study.

Enhanced coronary blood flow and abnormal blood flow in the aortic isthmus in severe fetal anemia.

Coronary arteries are not normally visualized by fetal echocardiograms. Reversal of flow in the transverse aortic arch is most often seen in association with severe coarctation. We describe a case of a near-term fetus whose fetal echocardiogram showed very prominent coronary arteries and severe reversal of flow in the transverse aorta suggestive of a coarctation who was postnatally confirmed to have normal intracardiac and aortic anatomy. We discuss the pitfalls in clinical diagnosis in this case to alert pediatric cardiologists of transient perturbations in physiology masquerading as heart disease.

[Neonatal ultrasonographic cerebral findings: association with risk factor for cerebral palsy]. / Stellenwert der postnatalen Neurosonographie für die frühzeitige Erfassung und ursächliche Klärung der Zerebralparese.

BACKGROUND: Is it possible to identify patients with cerebral palsy (CP) with postnatal ultrasound scan? Which risk factors are associated with an increased risk of CP?. PATIENTS AND METHODS: The data of 37 children with CP, who were sonographically investigated during the first 24 hours of life were analyzed retrospectively. The data of 21 preterm infants with gestational age /= 33 wk and in 5/8 of the mature babies. The mature babies had prenatal brain atrophy or hypoxic-ischaemic cerebral lesions. Cytomegaly and encephalitis were detected in two babies. Immature babies >/= 33 wk showed prenatal porencephaly or encephalomalacia after asphyxia. Premature babies