Vigintiphobia revisited.

In this review the historical tenets and evidence-based clinical research in support of a bilirubin exchange threshold of >20 mg/dL for the healthy term neonate are revisited. In addition, a hypothesis is ventured that recent cases of kernicterus are related in part to changes in population factors coupled with genetic predispositions that have unmasked an unappreciated potential for marked neonatal hyperbilirubinemia.

Stillbirths with placental hemorrhagic endovasculitis: a morphologic assessment with clinical implications.

CONTEXT: Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration affecting fetal-placental blood vessels of all calibers. Hemorrhagic endovasculitis is found in association with stillbirth and abnormalities of growth and development in livebirths. The role of HEV in the pathogenesis of these conditions is not known. OBJECTIVE: To further understand these events, we compare clinicopathologic features of HEV-affected placentas from stillbirths with those from livebirth pregnancies. Additionally, we assess the relationship of morphologic forms of HEV to clinical events and time of fetal death in utero and evaluate the significance of extensive versus localized HEV lesions in placentas of stillbirths. DESIGN: We reviewed the clinical records and slides from 119 stillbirths with placentas affected by HEV classified above a specified severity level (cases) and 119 matched stillbirths with placentas not affected by HEV (controls). A subset of 21 stillbirth placentas exhibiting focal HEV lesions was similarly evaluated. Slides were graded for HEV, villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and lesions indicative of maternal hypertension. Hemorrhagic endovasculitis was subcategorized into active, bland, and healed forms and clustered capillary lesions (hemorrhagic villitis). Focal, segmental, and diffuse patterns of villous fibrosis were delineated. Interlesional relationships were established by matching HEV severity indices with severity indices of co-existing lesions. Timing of fetal death was determined by published criteria. Data were analyzed for significance using chi2 and t tests. Results were compared with published analyses of livebirths with placental HEV. RESULTS: Lesions occurring with significant frequency in HEV-affected (case) placentas include villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and meconium staining. Interlesional relationships were evident between HEV and villous fibrosis, villitis of unknown etiology, and chorionic thrombi. Growth restriction was more common in case versus control infants (P = .02). A segmental pattern of villous fibrosis predominated in cases versus controls and within the case group (P < .001). Time to delivery after fetal death was longer in cases than controls. Active-vasodestructive forms of HEV correlate with shorter intervals of intrauterine retention, whereas bland forms correlate with longer intervals (P = .04). Placentas with focal HEV were associated with coexisting chorionic thrombi and villous fibrosis but not with fetal growth restriction. CONCLUSIONS: Patterns of interlesional interplay are similar in HEV-affected placentas of livebirths and stillbirths. This suggests that the pathogenesis of infant morbidity and mortality is similar in both groups. Active-vasodestructive forms of HEV may precede whereas bland forms may follow intrauterine demise. The segmental pattern of villous fibrosis and high incidences of growth restriction, erythroblastosis, and meconium in cases suggests a chronicity of adverse intrauterine events that may precede fetal loss. Stillbirths with focal HEV lesions are probably not at risk.

La transfusión intrauterina por cordocentesis: Una alternativa terapéutica con expectativa de vida / Intrauterine transfusion by cordocentesis: A therapuetic alternative with life expectancy

La enfermedad hemolítica por anti D es una grave problemática de nuestro medio que es reconocido como causa de muerte perinatal. Conociendo que las pacientes con enfermedad hemolítica severa, las posibilidades de viabilidad fetal son nulas a pocas semanas de gestación donde otros tratamientos no fueron suficientes, nuestro trabajo demuestra que la transfusión intrauterina por cordocentesis (TIUPC) es una técnica que logra alta expectativa de vida ya que permite no solo reabsorber el hidrops fetal alcanzando embarazos a término con fetos viables, sino también evolución de los recién nacidos sin necesidad de internaciones prolongadas, con menor costo, en relación a los gastos ocasionados por el manejo multidisciplinario que requerían los neonatos sin este tratamiento.

[Haemolytic disease of the newborn--from a mother with anti-Kell, anti-E and anti-Vel anti-erythrocyte alloantibodies]. / Morbus Haemolyticus Neonatorum (MHN) -- Hämolytische Krankheit des Neugeborenen von Mutter mit Anti-Kell, Anti-RhE und Anti-VEL Antierythrozytären Alloantikörpern.

A grave form of HDN (haemolytic disease of the new-born) is described in female twins, caused by Kell, E and Vel isoimmunisation. The weakly vital and anaemic new-born babies were hospitalised with signs of respiratory distress on the first day of their life after the delivery by Caesarean section in the 38 (th) week of pregnancy in the General Hospital Dubrovnik. Already during the first hours of their life jaundice developed with a high bilirubin level for their age. The direct Coombs' test on the twins and the indirect Coombs' test on the mother were positive. Immuno-haematological analysis proved the presence of anti-Kell, anti-E and the very rare anti-Vel antibodies in the mother's serum and in the plasma of both twins. We had no possibility to obtain appropriate blood for the indicated exsanguine transfusion because cross-probes with the accessible blood samples were positive. Up to the fourteenth day of life the anaemia deepened and was aggravated in one twin, the Kell positive one (phenotype CcDEe,Kk) in relation to the other, the Kell negative (phenotype CcDEe,kk) twin. The recovery of the female twins started on the 15 (th) day of life, after the transfusion of blood (phenotype: 0,ccddee, Vel negative, Kel negative), received from the bank of rare blood groups in London. This is the first described case of haemolytic disease of the new-born caused by antibodies on the antigen Kell, E and Vel. The low frequency of immunisation with rare antigens such as Kell, E and Vel, does not exclude the possibility of the occurrence of grave forms of haemolytic disease. All pregnant women with a positive indirect Coombs' test should be further immuno-haematologically tested in order to identify the antibodies type so that the treatment of the new-borns could be commenced in time.

Increased fetal iron load in rhesus hemolytic disease.

There is little information about the iron overload caused by hemolysis in fetuses affected with rhesus hemolytic disease (RHD). The authors therefore studied the iron load in RHD by measuring cord blood ferritin levels in babies affected with RHD and gestational age- and weight-matched controls. Cord blood ferritin levels were higher in babies with RHD. Intrauterine transfusions did not affect the ferritin status of the babies with RHD and there was no correlation between hemoglobin and ferritin levels. The results indicate that there is an increased intrauterine iron load in babies with RHD, independent from intrauterine transfusions and rate of hemolysis.

Neonatal jaundice: physiologic variation or pathologic process.

Neonatal hyperbilirubinemia and jaundice affect approximately 60% of the 4 million newborns in the United States each year. Jaundice results from bilirubin deposition in the skin and mucous membranes, becoming clinically visible at a serum bilirubin level of 5 to 7 mg/dL. At a higher but undefined level, bilirubin may deposit in the brain where it can cause transient dysfunction or permanent neurologic impairment.

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

An early (sixth-hour) serum bilirubin measurement is useful in predicting the development of significant hyperbilirubinemia and severe ABO hemolytic disease in a selective high-risk population of newborns with ABO incompatibility.

OBJECTIVE: In the era of early discharge of newborns from the hospital, newborns with ABO incompatibility are at especially greater risk for developing a subsequent significant hyperbilirubinemia because some of these infants also may present with some degree of ABO isoimmune disease. In this study, we aimed to determine prospectively the critical serum total bilirubin level to predict significant hyperbilirubinemia and severe hemolytic disease in healthy term newborns with ABO incompatibility based on a serum bilirubin measurement made at a postnatal age at which all newborns are at the hospital before discharge and at which any therapeutic intervention, if necessary, could be started as early as possible. METHODS: A total of 136 healthy term newborns with ABO (O-A or O-B) blood group incompatibility were followed prospectively with daily serum total bilirubin measurements for the first 5 days of life. Newborns with serum total bilirubin levels of > or =5 mg/dL and an increase in serum total bilirubin concentration of >0.5 mg/dL/h in the first 24 hours, > or =12 mg/dL on day 2, > or =15 mg/dL on day 3, and > or =17 mg/dL on days 4 and 5 were defined to have significant hyperbilirubinemia and were started on phototherapy treatment. Additional treatment modalities, including intense phototherapy, intravenous immunoglobulin treatment, and exchange transfusion, were used when serum bilirubin concentrations exceeded 20 mg/dL or increased by >1 mg/dL/h despite a phototherapy treatment of at least 4 hours. The additional assessment of the predictive ability of the sixth-hour serum total bilirubin value in determining the development of significant hyperbilirubinemia was made on the basis of the placement of any of the first 5 days' serum bilirubin measurements in the > or =90th percentile of the study population. On the basis of the percentile tracks constructed from the 10th, 35th, 50th, 60th, and 90th percentiles of serum total bilirubin values, a nomogram demonstrating the 3 percentile tracks as risk zone demarcators with divided risk zones was produced. RESULTS: Twenty-nine newborns (21.3%) had significant hyperbilirubinemia. There were significant differences between the newborns who did and the newborns who did not develop significant hyperbilirubinemia with respect to the reticulocyte count (4.39 +/- 3.46% vs 2.95 +/- 1.63) and the presence of a direct antiglobulin test positivity (6 of 23 vs 0 of 107) and a sibling with neonatal jaundice (6 of 23 vs 5 of 102). A mean serum bilirubin level of > or =4 mg/dL at the sixth hour of life was determined to have the highest sensitivity (86.2%) and negative predictive value (94.5%) and a positive predictive value of 39.7% to predict the newborns who would develop significant hyperbilirubinemia. At the mean serum bilirubin level of 6 mg/dL, the sensitivity, specificity, and negative and positive predictive values were 100%, 91.5%, 100%, and 35.3%, respectively, in diagnosing 6 cases of severe ABO hemolytic disease. On the hour (age)-specific percentile-based nomogram, the zone above the 90th percentile was determined as high risk and that below the 35th percentile as low risk. CONCLUSIONS: The reticulocyte count, a positive direct antiglobulin test, and the presence of a sibling with neonatal jaundice were determined to be the good predictors for the development of significant hyperbilirubinemia and severe hemolytic disease of the newborn. A serum bilirubin measurement and the use of the critical bilirubin levels of 4 mg/dL and 6 mg/dL at the sixth hour of life will predict nearly all newborns who will have significant hyperbilirubinemia and those who will develop severe hemolytic disease of the newborn, respectively. An hour (age)-specific percentile-based nomogram can be used to predict which newborn is at high risk (> or =90th percentile), intermediate risk (35th-90th percentiles), and low risk (<35th percentile) for developing significant hyperbilirubinemia. The 35th and 90th percentile tracks, approximating the serum bilirubin levels of 3.3 mg/dL and 6.5 mg/dL at the sixth hour of life, respectively, can be used as safe risk demarcators in deciding about the time of discharge of ABO-incompatible newborns from the hospital.

Correction of fetal anemia on the middle cerebral artery peak systolic velocity.

OBJECTIVE: To assess the effect of correction of fetal anemia on the middle cerebral artery peak systolic velocity values. METHODS: With Doppler ultrasonography, middle cerebral artery peak systolic velocity was measured in 41 fetuses before and immediately after 54 intrauterine transfusions for severe red blood cell alloimmunization. The fetuses were divided into two groups: 17 fetuses studied at first transfusion (group A), and 24 fetuses enrolled to the study after the first transfusion (group B). Both fetal hemoglobin and middle cerebral artery peak systolic velocity were plotted over the respective reference ranges as a function of gestational age. Both values were expressed as multiples of the median and analyzed with paired t test. RESULTS: The values of middle cerebral artery peak systolic velocity decreased in all but one fetus of group B (P <.05). The values of middle cerebral artery peak systolic velocity before transfusion were above the upper limit of the reference range in 60% of the fetuses of group A and in 38% of group B, respectively. After correction of anemia, only one value remained above the upper limit of the reference range. CONCLUSION: The correction of fetal anemia with intrauterine blood transfusion decreases significantly and normalizes the value of the fetal middle cerebral artery peak systolic velocity.

Complementary therapy for severe Rh-alloimmunization.

PURPOSE OF INVESTIGATION: This report describes successful treatment, using invasive and noninvasive techniques, of a 36-year-old woman (gravida 10, para 0) referred to our center at 13 weeks' gestation for severe Rh alloimmunization. Pre-pregnancy indirect Coombs titers ranged from 1:1024-2048. All nine past pregnancies (conceived with three different partners) had ended in abortion, intrauterine death or neonatal death METHODS: The patient was treated with a single session of plasmapheresis (week 14) immediately followed by five days of immunoglobulin therapy and immunosuppressive therapy based on azathioprine and prednisone (weeks 15-22). Seven fetal transfusions (one intraperitoneal, six intravascular) were performed beginning at 16 weeks. RESULTS: The pregnancy, which was characterized by insulin-dependent gestational diabetes, spontaneously resolving polyhydramnios and peak indirect Coombs titers of 1:65,536, ended at 27 weeks with cesarean section delivery of a viable female weighing 1,000 g. In spite of numerous neonatal complications, the child is physically well at age 3, with normal intellectual and psychomotor development. CONCLUSION: In light of the negative outcomes of the patient's nine past pregnancies, our experience suggests that the early initiation of an integrated approach based on noninvasive and invasive techniques can play a potentially decisive role in the management of severe Rh-alloimmunization.

Doppler ultrasound velocimetry for timing the second intrauterine transfusion in fetuses with anemia from red cell alloimmunization.

OBJECTIVE: Middle cerebral artery peak systolic velocity has been successfully used for timing the first cordocentesis in fetuses who are at risk for anemia because of maternal red cell alloimmunization. The effects on Doppler velocimetry after the intrauterine transfusion of adult blood to these fetuses are unknown. The objective of this study was to assess the applicability of Doppler methods for the prediction of severe anemia in fetuses who had undergone 1 previous intrauterine transfusion. STUDY DESIGN: Doppler examination of middle cerebral artery peak systolic velocity was performed before cordocentesis in 64 fetuses who had undergone 1 previous intrauterine transfusion. Timing of the second intrauterine transfusion was based on traditional criteria. Anemia was defined as mild (hemoglobin value between 0.84 and 0.65 multiples of the median), moderate (hemoglobin value <0.65-0.55 multiples of the median), and severe (hemoglobin value <0.55 multiples of the median). Receiver operator characteristic curves were created to select threshold values to identify the 3 degrees of anemia with a sensitivity of 100%. RESULTS: Gestational age at the Doppler study ranged from 19 to 36 weeks. Forty-six fetuses (72%) were not or mildly anemic; 7 fetuses (11%) were moderately anemic, and 11 fetuses (17%) were severely anemic. Middle cerebral artery peak systolic velocity for the prediction of severe, moderate, and mild anemia at a sensitivity of 100% showed false-positive rates of 6%, 37%, and 70%, respectively. CONCLUSION: In fetuses who have undergone 1 previous intrauterine transfusion because of maternal red cell alloimmunization, timing the second intrauterine transfusion can be determined noninvasively by Doppler ultrasonography on the basis of an increase in the peak velocity of systolic blood flow in the middle cerebral artery.

Prediction of fetal anemia with Doppler measurement of the middle cerebral artery peak systolic velocity in pregnancies complicated by maternal blood group alloimmunization or parvovirus B19 infection.

OBJECTIVES: To confirm the relationship between the middle cerebral artery peak systolic velocity (MCA PSV) and hemoglobin values in fetuses at risk for anemia (due to maternal blood group alloimmunization or parvovirus B19 infection) and to investigate the clinical value of this method in the management of these pregnancies regardless of previous transfusions. SUBJECTS AND METHODS: Forty singleton pregnancies, 30 affected by alloimmunization and 10 by intrauterine parvovirus B19 infection, were referred to our tertiary center between 1998 and 2000. All cases underwent Doppler measurement of the MCA PSV immediately before fetal blood sampling and just before and after intrauterine transfusion. Hemoglobin determination was always performed after diagnostic cordocentesis, before starting and after terminating fetal transfusion. RESULTS: Overall, we performed 165 fetal blood samplings (hemoglobin values) and obtained 165 corresponding MCA PSV values, 140 in pregnancies complicated by red-cell alloimmunization and 25 by parvovirus B19 infection. In order to adjust for the effect of gestational age on the measurements, the data were expressed in multiples of the median (MoM). We found a good correlation between MCA PSV MoM and Hb MoM in both groups (alloimmunization, r2 = 0.6; y = 2.21 - 1.41 x + 0.24 x 2; parvovirus infection, r2 = 0.68; y = 2.09 - 0.58 x - 0.16 x 2). The reduction of post-transfusion MCA PSV values was statistically significant ( P < 0.0001). Using a threshold of 1.29 for MoM PSV, the sensitivity and the specificity of MCA pulsatility indices on pretransfusion values in predicting any degree of fetal anemia (Hb < or = 0.84 MoM) were 73.1% and 81.5% in the alloimmunization group and 100% and 100% in the parvovirus infection group, respectively. CONCLUSION: We can confirm the presence of an inverse correlation between MCA PSV measurements and hemoglobin values in fetuses at risk for anemia due to maternal blood group alloimmunization and fetal parvovirus B19 infection. The MCA PSV is a reliable method for the prediction of anemia not only in fetuses before the first intrauterine transfusion, but also in those which have undergone one or more transfusions, with good sensitivity and specificity in both groups of fetuses at risk.

Massive fetomaternal transplacental hemorrhage as a perinatology problem, role of ABO fetomaternal compatibility--case studies.

BACKGROUND: Massive fetomaternal transplacental hemorrhage is not simply a problem of possible alloimunization in Rh incompatibility but also endangers the fetus (newborn) by massive anemization. Bleeding from placental vessels can occur after small trauma to the gravid uterus with mild or no clinical signs (bleeding or spotting, pain, hypertonus). The rupture of anchoring villi related to early uterine contractions is also possible. In the case of slow blood loss, the fetus reacts by adequate or inadequate compensatory reactions (hydrops fetus). Rapid and massive blood loss is followed by perinatal hypoxic damage and finally death. Our goal was to map out the diagnostic and therapeutic possibilities in regard to specific neonatal care. CASE REPORT: We evaluated four cases of fetomaternal transfusion during a 2-year period with special regard to postpartum adaptation of the newborn and the perinatal outcome. The incidence of adverse outcomes following massive fetomaternal transplacental hemorrhage was 50% (2 of 4). There was one perinatal death and one infant was affected by spastic quadriplegia. CONCLUSIONS: For diagnosis, it is possible to use cardiotocography (decreased variability, sinusoid pattern), ultrasound (biophysical profile) and special hematological tests for quantitative determination of fetal erythrocytes in the maternal blood. For the treatment of such cases one should consider premature termination of pregnancy or intraumbilical transfusion.

[Blueberry muffin baby: the pathogenesis of cutaneous extramedullary hematopoiesis]. / Blueberry-Muffin-Baby. Zur Pathogenese der kutanen extramedullären Hämatopoese.

Two neonates exhibited the clinical picture of the "blueberry muffin baby" at delivery. The integument manifested petechiae and purpuric magenta-colored macules, papules, and plaques, as well as blueberry-colored ecchymoses. These findings led to the diagnosis of a connatal cytomegalovirus infection and fetal erythroblastosis, respectively. The hemorrhagic-purpuric looking skin lesions reflected extramedullary hematopoiesis with ultrastructural study disclosing evidence of both erythro- and granulopoietic lineage. For the first time, we were able to demonstrate that complexes of red cells in various stages of maturation can occur in the skin, similarly to the erythroblastic islands of the bone marrow. In the pathogenesis of extramedullary hematopoiesis, mechanisms underlying the reconstitution of blood cells must be considered. These may reactivate hematopoiesis in organs where it previously occurred in embryonic and fetal life. Possible causative factors may be great compensatory demand, deficient replacement, or loss or dysfunction of corpuscular blood elements. This would explain the occurrence of this disease entity in conjunction with etiologically completely heterogeneous systemic diseases.

Neonatal exchange transfusion: a Jordanian experience.

The aetiology and complications of exchange transfusion (ET) were studied over a 6-year period in northern Jordan. During that time, 336 neonates (0.46% of total live births) underwent 386 ETs. There was a yearly reduction in the number of ETs, varying from 8.2% in the 1st year of the study to 2.7% in the last year. Thirty-nine (11.9%) required more than one ET. Twenty-five (7.4%) were preterm babies and the remainder full-term. The commonest cause of ET overall was G6PD deficiency, either alone or concomitant with ABO incompatibility (38.1%). ET complications occurred in 51 neonates (15.2%), the commonest being anaemia and bradycardia. Septicaemia occurred in only 3% of cases. Only one baby died. G6PD deficiency, either alone or concomitant with ABO isoimmunization, is the most common cause of ET in northern Jordan. Fewer preterm babies require ET and there is a low incidence of septicaemia following ET.

Sonographic methods to detect fetal anemia in red blood cell alloimmunization.

Published reports, case studies, and articles from the English language regarding ultrasonographic detection of fetal anemia in red blood cell alloimmunization were obtained from a MEDLINE search from 1966 to November 1999 using the keywords Rh disease, hemolytic disease of the newborn, ultrasound, and Doppler flow studies and combinations thereof. All articles were cross-referenced. Ultrasound techniques including early findings associated with immune hydrops fetalis, multiple morphologic ultrasound markers, and Doppler flow studies that have been used to detect fetal anemia are reviewed and critically evaluated. Noninvasive sonographic techniques may reduce the number of invasive procedures that traditionally are used to follow fetuses at risk for anemia and decrease the associated risks from these procedures.

Perinatal management of fetal hemolytic disease due to Rh incompatibility combined with fetal alloimmune thrombocytopenia due to HPA-5b incompatibility.

We report out experience in the perinatal management of a complex case of fetal hemolytic disease primarily due to Rhesus incompatibility combined with fetal alloimmune thrombocytopenia. The lowest fetal hemoglobin and platelet levels were 2.6 g/dl and 13,000/microliter, respectively. Intrauterine treatment consisted of six transfusions of packed red cells into the umbilical vein and one transfusion of platelets. The neonate required four transfusions of packed red cells to correct her hyporegenerative erythropoiesis. Postnatal management also included one platelet transfusion, intravenous immunoglobulins and erythropoietin. Although some degree of fetal thrombocytopenia may invariably be found in fetal red cell incompatibility, other rare causes need to be excluded.

Serum malondialdehyde concentration in babies with hyperbilirubinaemia.

AIM: To determine lipid peroxide concentrations in the first 10 days of life. METHODS: Malondialdehyde concentrations were investigated in neonates with or without hyperbilirubinaemia during the first 10 days of life. RESULTS: Serum malondialdehyde concentrations were higher in infants with hyperbilirubinaemia than in controls. A positive correlation was found between malondialdehyde and bilirubin concentrations in the study group. When the study group was categorised according to the presence of haemolysis, a significant correlation was found between malondialdehyde and bilirubin concentrations in those infants with hyperbilirubinaemia due to haemolysis. There was no such correlation in those without haemolysis. CONCLUSION: Exchange transfusion rapidly produces variable changes in pro-oxidant and antioxidant plasma concentrations in neonates, which may be responsible for free radical metabolism. The fall in malondialdehyde concentration is probably directly related to its exogenous removal by exchange transfusion.