Evaluation of Rh-Hemolytic Disease in Neonates and Management with Early Intensive Phototherapy in the Neonatal Intensive Care Unit.

BACKGROUND OF THE STUDY: In neonates with Rh-hemolytic disease, light emitting diode (LED) phototherapy allows delivery of high spectral irradiance (SI). A linear correlation exists between SI and efficacy of phototherapy with no saturation point. There is scant data on evaluation and early phototherapy using LED units in Rh-hemolytic disease. OBJECTIVE: This study aimed to describe the hemoglobin (Hb), hematocrit (Hct), total serum bilirubin (TSB), phototherapy parameters and short-term outcomes in neonates with Rh-hemolytic disease. METHODOLOGY: Maternal parameters for Rh-isoimmunization were recorded and monitoring of fetal anemia by Doppler ultrasound was done. Early intensive phototherapy within 1 h of birth was initiated for cord blood Hb below 13.6 g/dl and/or TSB greater than 2.8 mg/dl. RESULTS: Fifty Rh positive neonates were enrolled of which 11/50 (22%) received intrauterine transfusions. The maximum TSB remained below 18 mg/dl in 42/50 (84%) of neonates. The mean SI on the trunk was 56.260 ± 8.768 µW/cm2/nm and duration of phototherapy was 7 ± 3.29 days (mean ± SD). There was a positive correlation between strength of indirect antiglobulin test and cord blood Hb: correlation coefficient (r) = 0.295; direct antiglobulin test and duration of phototherapy: r = 0.331. Early packed red blood cell (PRBC) transfusion was required in 8/50 (16%) neonates while 20/50 (40%) required late transfusions. CONCLUSION: With a mean SI of 56.260 ± 8.768 µW/cm2/nm on the trunk, TSB remained below 18 mg/dl in majority thereby avoiding exchange transfusion. Early or late PRBC transfusion requirement was 1 (1-2) (median ± interquartile range).

X-ray Study of Human Dental Tissues Affected by Erythroblastosis Fetalis.

Numerous diseases are known to cause microstructural alteration of dental tissues structure. One type in particular is associated with neonatal jaundice and circulation of bilirubin in blood at high concentration due to increased hemolysis in conditions such as erythroblastosis fetalis, septicemia, biliary atresia, and other causes of hyperbilirubinemia. In those conditions, the products of the catabolism of hemoglobin end up deposited in various tissues, including teeth, where they can present clinically as visibly stained brown/green teeth. There is almost no information on the nature or extent of the structural changes taking place in these conditions. Here, advanced nondestructive wide-angle synchrotron X-ray scattering techniques combined with scanning microscopy methods were used to investigate for the first time the ultrastructure of the dental hard tissues in an archival case of intrinsically pigmented green teeth. Despite no obvious elemental variation across the pigmented tissue region, the high-resolution crystallographic properties probed by wide-angle synchrotron X-ray scattering revealed an ultrastructural variation (orientation, particle size, and lattice parameter of hydroxyapatite crystallites) associated with a pigmentation line in dentine and with a distinct neonatal line in enamel.

Transient neonatal hyperinsulinism with adaptation disorders: a report of three cases.

Transient hyperinsulinism can occur in neonates following exposure to perinatal stress, such as intrauterine growth restriction and birth asphyxia. However, little is known about its pathophysiology and clinical manifestations. We report three neonatal cases of transient severe hyperinsulinism complicated with cardiopulmonary problems, thrombocytopenia, and marked erythroblastosis at birth. All cases showed signs of placental insufficiency, indicating that chronic hypoxia and malnutrition during fetal development might be associated with characteristic clinical features after birth. Perinatal stress-associated hyperinsulinism can be regarded as a systemic syndrome characterized by cardiopulmonary and hematological problems due to fetal chronic hypoxia.

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.

Noninvasive approach for the management of hemolytic disease of the fetus.

Hemolytic disease of the fetus and newborn (HDFN) is due to maternal alloantibodies directed against paternally inherited antigens on fetal red cells, and it is still a problem in affected pregnancies despite the routine use of anti-D immunoglobulin during pregnancy and shortly after delivery. The current noninvasive management of HDFN starts with the determination of fetal RhD genotype by use of cell-free fetal DNA in maternal plasma. When the fetus is antigen positive, the follow-up is performed by Doppler ultrasonography for the detection of moderate or severe anemia on the basis of an increase peak velocity of systolic blood in the middle cerebral artery. Finally, if anemia is suspected, an invasive approach is required in order to perform an intrauterine blood transfusion, which should only be attempted when the fetus needs transfusion. This approach reduces the iatrogenic conversion of mild-to-severe disease, which occurred as a result of the previous invasive management, and prevents unnecessary administration of human-derived blood products. These changes represent one of the genuine successes of fetal therapy.

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.

Update on the management of non-anti D antibodies.

With the development of the Rh D immunoglobulin and utilisation in clinical practice, severe rhesus iso-immunisation is rarely seen today. Antibodies against other blood groups are now more common than anti-D and while the majority do not cause significant haemolysis, there are reports of serious morbidity with antibodies other than anti-D. We reviewed retrospectively all cases (excluding anti-D and anti kell antibodies) where antibodies were detected at routine booking visit between 1997-2001 and correlated the type of antibody to clinical outcome as assessed by coombs test, postnatal phototherapy and transfusion. Our approach to these cases does not involve invasive test as amniocentesis and relies on the ultrasound monitoring, level of antibodies and timely delivery with appropriate paediatric follow up. Over five years period 150 women were identified with antibodies other than anti-D or anti-kell. There were no directly related deaths. Many authorities suggest amniocentesis for specific antibodies to assess fetal haemolysis and plan management. This study support a non-invasive approach with mortality and minimal morbidity.

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.

[Contribution of Doppler examination in pregnancy at risk of alloimune fetus anemia]. / Prínos dopplerovského vysetrení pro tehotenství s rizikem alloimunní anémie plodu.

OBJECTIVE: To evaluate the utilisation measurements of peak systolic velocities in the middle cerebral artery (MCA-PSV) to predict fetal anemia in pregnancies complicated by alloimmune antibodies known to cause immunological hydrops. DESIGN: A prospective study. SETTING: Department of Obstetrics and Gynecology, University Hospital, Olomouc. METHODS: In 38 pregnancies at risk for fetal anemia due to maternal red-cell alloimmunization MCA-PSV had been assessed and fetal blood sampling for measurement of hemoglobin concentration was obtained subsequently, either by cordocentesis or at delivery. RESULTS: 66 examinations were performed at 19-37 week's gestation. An MCA-PSV >1.5 MoM detected 100% of severely anemic fetuses with a hemoglobin concentration <0.65 MoM that required invasive intervention. In 18 cases a cordocentesis was performed and intrauterine blood transfusion was given alternatively. Remaining fetuses did not require invasive intrauterine intervention and no or mild hemolytic anemia and hyperbilirubinemia were diagnosed after delivery. No false positive case was identified (enregistered). The median maternal age at the term of delivery was 29.1 (range, 19-41) years. CONCLUSION: Middle cerebral artery peak systolic velocity is a highly sensitive non-invasive means for determining the degree of anemia. A Doppler interval of seven days is recommended.

Non-invasive tests to predict fetal anemia in Kell-alloimmunized pregnancies.

OBJECTIVES: To compare test characteristics of ultrasound and Doppler parameters in the prediction of fetal anemia in Kell-alloimmunized pregnancies. METHODS: In this prospective study, 27 fetuses at risk for anemia due to Kell alloimmunization were evaluated with ultrasound and Doppler imaging. Spleen perimeter, liver length, middle cerebral artery (MCA) peak systolic velocity and intrahepatic umbilical venous (IHUV) maximum velocity were measured. Results were compared with fetal hemoglobin values at first intrauterine blood sampling or delivery. Severe fetal anemia was defined as a hemoglobin deficit of at least 5 SD below the mean for gestational age. RESULTS: Eighteen fetuses were anemic and required intrauterine transfusions. In the other nine pregnancies no transfusions were performed; one of these fetuses was severely anemic at birth. MCA and IHUV flow velocities were the best predictors of fetal anemia in Kell alloimmunized fetuses (sensitivity 89% for each test). Sensitivities for spleen perimeter (15%) and liver length (14%) were disappointing. CONCLUSIONS: Doppler evaluation of MCA peak systolic velocity and IHUV maximum velocity can be used to reliably predict severe fetal anemia in Kell alloimmunization.

Comparison of different reference values of fetal blood flow velocity in the middle cerebral artery for predicting fetal anemia.

OBJECTIVES: To compare different normal reference ranges of fetal blood flow velocity in the middle cerebral artery for predicting fetal anemia. METHODS: Eight reference ranges of either middle cerebral artery peak or time-averaged mean velocities were compared using the area under the receiver-operating characteristics (ROC) curve for 113 fetal blood samples from 60 women at risk of fetal red blood cell alloimmunization. RESULTS: The areas under the ROC curves of the different ranges were not significantly different but there were marked differences in sensitivity (range, 7.14-91.78%) and specificity (range, 31.25-96.88%) with the currently used cut-offs. Except for Mari's range, the best theoretical cut-offs, defined as those having the best sensitivity with the best specificity, differed from those in current use, especially when using time-averaged mean velocity. CONCLUSIONS: Any of the previously reported reference ranges perform well in the non-invasive prediction of fetal anemia. However, with the exception of Mari's curve, the currently employed cut-offs for predicting fetal anemia should be changed, some of them markedly, in order to provide reliable support for clinical decisions.

[Doppler ultrasound to detect Rh: a systematic review]. / Ultrasonido doppler para detección rh: una revisión sistemática.

BACKGROUND: Red cell alloimmunization is an important cause of perinatal morbidlity and mortality. Invasive procedures used to diagnose fetal anemia are associated with serious fetal and maternal complications. The development of noninvasive techniques as Doppler ultrasound can help us in the fetal anemia diagnosis. OBJECTIVES: To evaluate the effect of the Doppler ultrasound in prediction of fetal anemia caused by red cell alloimmunization. Strategy search: Relevant studies were identified by reviewing the registry of COCHRANE, and OVID, PROQUEST, MEDLINE and EMBASE data bases from 1966 to 2004. SELECTION CRITERIA: All prospective studies with clinically relevant results with comparison of Doppler ultrasound in fetal umbilical artery, fetal descendent aorta, middle cerebral fetal artery or esplecnic fetal artery with hemoglobin or fetal hematocrit. DATA COLLECTION AND ANALYSIS: Data were extracted from each report. The quality revision of the studies and the data compilation were made by the reviewers. MAIN RESULTS: Eighteen articles were included. Two studies reached the level of evidence 1 for diagnostic tests. The diagnostic tests had variations depending on the different cut-off of each study. Studies with level 1 of evidence reported detection of 100% for moderate to severe fetal anemia. CONCLUSIONS: Implementation of Doppler ultrasound for prediction of fetal anemia in complicated pregnancies with alloimmunization could reduce the number of invasive procedures and therefore its complications. The level of present evidence reveals to us that the studies do not fulfill the criteria of methodological quality.

Massive fetal ascites causing increased middle cerebral artery systolic velocity.

BACKGROUND: An elevated peak systolic velocity in the middle cerebral artery, assessed by Doppler ultrasonography, is commonly associated with fetal anemia. Other fetal abnormalities associated with a high middle cerebral artery velocity have rarely been reported. CASE: A fetus with increasing ascites was found to have an elevated middle cerebral artery peak systolic velocity. Following paracentesis, the peak systolic velocity normalized. Peak systolic velocity continued to correlate with the level of ascites, falling to normal ranges when large-volume amniocentesis and paracentesis were performed. At birth, the infant was found to have a normal hematocrit. CONCLUSION: An elevated middle cerebral artery peak systolic velocity may result from massive fetal ascites without anemia. We hypothesize that the massive ascites led to increased afterload of the heart, with relatively preserved preload, leading to an increased systolic blood pressure and an elevated middle cerebral artery peak systolic velocity.

Sonographic demonstration of brain injury in fetuses with severe red blood cell alloimmunization undergoing intrauterine transfusions.

OBJECTIVE: To assess sonographically brain anatomy in fetuses with severe anemia due to red blood cell alloimmunization undergoing intrauterine intravascular transfusions. METHODS: Multiplanar neurosonography was performed in seven consecutive hydropic fetuses undergoing intrauterine transfusions (mean gestational age 22 +/- 2.5 weeks; mean hemoglobin concentration at the first transfusion 2.3 +/- 1.0 g/dL). RESULTS: Abnormal cerebral findings were identified in four out of seven fetuses. An intracerebellar hemorrhage developed in two fetuses after the first transfusion and one fetus that had severe brain edema before the first transfusion was later found to have cystic periventricular leukomalacia. In one fetus unilateral ventriculomegaly was noted after the first transfusion. Two fetuses were terminated. The remaining pregnancies had an uneventful course, the infants were delivered between 34 and 36 gestational weeks and were alive and well at the time of writing. Prenatal diagnosis of brain injury was always confirmed except for the case with ventriculomegaly that underwent spontaneous intrauterine resolution. CONCLUSIONS: Fetuses with extreme anemia due to red blood cell alloimmunization can be salvaged by intrauterine transfusion. In some of these cases brain injury may occur prenatally, and the risk seems to be particularly high when the hemoglobin concentration at the time of the first transfusion is

Prediction of fetal anemia in rhesus disease by measurement of fetal middle cerebral artery peak systolic velocity.

OBJECTIVE: In red blood cell (RBC) isoimmunized pregnancies fetal anemia is associated with a hyperdynamic circulation. The aim of the present study was to examine further the possible value of fetal middle cerebral artery peak systolic velocity (MCA-PSV) in the management of affected pregnancies. METHODS: A reference range of fetal MCA-PSV with gestation was constructed from the study of 813 normal singleton pregnancies at 20-40 weeks' gestation. Fetal MCA-PSV was also measured in 58 fetuses from RBC isoimmunized pregnancies, with maternal hemolytic antibody concentration of >15 IU/mL at 19-38 weeks' gestation and within 10 days of measurement of fetal hemoglobin concentration in blood obtained either by cordocentesis (n = 43) or at delivery (n = 15). In the RBC isoimmunized pregnancies each of the measured MCA-PSV and hemoglobin concentrations was expressed as a delta value (difference in SDs from the normal mean for gestation). Regression analysis was used to determine the significance of the association between delta MCA-PSV and delta fetal hemoglobin concentration. RESULTS: In the normal pregnancies there was a significant increase in fetal MCA-PSV with gestation (mean MCA-PSV = 10(0.0223 x GA + 0.963)). In RBC isoimmunized pregnancies the fetal MCA-PSV was increased and there was a significant association between delta MCA-PSV and delta hemoglobin concentration (delta hemoglobin = (delta MCA-PSV + 0.093)/-0.356; R(2) = 0.638, P < 0.0001). An MCA-PSV of mean + 1.5 SDs detected 96% of severely anemic fetuses, with a hemoglobin deficit of at least 6 SDs, for a false-positive rate of 14%. CONCLUSION: Measurement of fetal MCA-PSV is a useful method of assessing fetal anemia. In the clinical management of isoimmunized pregnancies a cut-off in MCA-PSV of mean + 1.5 SDs can identify nearly all severely anemic fetuses with a low false-positive rate.

Predicting the severity of fetal anemia using time-domain measurement of volume flow in the fetal aorta.

OBJECTIVES: To assess the value of fetal aortic time-domain measurement of volume flow (using color velocity imaging quantification (CVI-Q)) in predicting the severity of fetal anemia. METHODS: This was a prospective observational study, in which 24 pregnant women with suspected fetal anemia due to rising anti-red blood cell antibody titers underwent cordocentesis. The fetal aortic time-domain volume flow was measured before fetal blood sampling for fetal hemoglobin investigation. We examined the correlation between increased fetal aortic time-domain volume flow (>2 SD for gestational age) and fetal anemia (hemoglobin level <2 SD for gestational age). RESULTS: Seventeen fetuses had anemia, and seven had normal hemoglobin. There was a strong correlation between the increase in fetal aortic time-domain volume flow and the drop in hemoglobin value (r = 0.81; P < 0.01). The sensitivity of this technique to predict fetal anemia was 81.3% and the specificity was 71.4%. The mean increase over time in aortic CVI-Q in anemic fetuses was 323.2 mL/min (95% CI, 200.1 to 446.4) compared with 86.9 mL/min (95% CI, -17.7 to 191.5) in the non-anemic group (P = 0.004). CONCLUSION: Fetal aortic time-domain measurement of volume flow is significantly increased in cases of fetal anemia due to red-cell alloimmunization. These findings can be used to improve the sensitivity, specificity and positive predictive value of the non-invasive techniques used to predict fetal anemia, and may help in the selection of pregnancies that require cordocentesis and transfusion.