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Background: The absence of the red cell antigens P, P1 and P k , known as 'p', represents an extremely rare red cell phenotype. Individuals with this phenotype spontaneously form anti-PP1P k isoantibodies, associated with severe haemolytic transfusion reactions, recurrent spontaneous abortion and haemolytic disease of the fetus and newborn (HDFN)., Methods: We report a series of four successful pregnancies in three women with anti-PP1P k isoantibodies, one complicated by HDFN, another by intrauterine growth restriction, all managed supportively. We also review the literature regarding the management of pregnancy involving anti-PP1P k isoimmunization., Results: The literature surrounding anti-PP1P k in pregnancy is limited to a very small number of case reports. The majority report management with therapeutic plasma exchange (TPE) with or without intravenous immunoglobulin. The relationship between titre and risk of pregnancy loss remains unclear, though a history of recurrent pregnancy loss appears important. Although a positive cord blood direct antiglobulin test is frequently noted, clinically significant HDFN appears uncommon, though possible., Conclusion: Early initiation of TPE in high risk patients should be strongly considered. If possible, pregnancies should be managed in a high-risk obstetric or maternal fetal medicine service. The fetus should be monitored closely with interval fetal ultrasound and middle cerebral artery peak systolic volume Doppler to screen for fetal anaemia. Timely sourcing of compatible blood products is likely to be highly challenging, and both directed and autologous donation should be contemplated where appropriate. The International Red Cell Donor Panel may also provide access to compatible products., (© 2020 International Society of Blood Transfusion.)

Anti-G is commonly present with anti-D and anti-C and can confuse serological investigations. The differentiation of anti-G from anti-D and anti-C is particularly essential for the accurate diagnosis of hemolytic disease of the fetus and newborn (HDFN) and appropriate administration of anti-D immunoglobulin prophylaxis in Rhesus (Rh) negative women. We reported a rare case of anti-G together with anti-D and anti-C in a pregnant woman and her female neonate. The titers of IgG anti-D, anti-C, and anti-G in the woman were 256, 128, and 32, respectively. While the titers of IgG anti-D, anti-C, and anti-G in the neonate were 16, 8, and 4, respectively. The neonate experienced mild HDFN and only received phototherapy during hospitalization. This report discusses the diagnostic strategy and clinical significance of differentiating anti-G from anti-D and anti-C., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pregnancy in women with sickle cell disease (SCD) is associated with increased maternal and fetal morbidity and mortality. Outcomes vary widely owing to methodological limitations of clinical studies, but overall, hypertensive disorders of pregnancy, venothromboembolism, poor fetal growth, and maternal and perinatal mortality are increased globally. Few therapeutic interventions have been explored other than prophylactic and selective transfusion therapy. Unfortunately, existing data are limited, and it remains unclear whether prophylactic use of chronic transfusions will improve pregnancy outcomes. Management of pregnant women with SCD is best accomplished with a multidisciplinary team that includes a sickle cell expert and an obstetrician familiar with high-risk pregnancies. Women with SCD should have individualized care plans that outline management of acute pain and guidelines for transfusion therapy. Neonates require close monitoring for neonatal abstinence syndrome and hemolytic disease of the newborn. Ideally all young women with SCD will have a "reproductive life plan" developed as a component of preconception counseling and health promotion. Research leading to improved pregnancy management focused on diminishing adverse maternal and neonatal outcomes is overdue. International collaborations should be considered to improve subject recruitment and foster timely completion of clinical trials. Additional therapeutic interventions outside of transfusion therapy should be explored., Competing Interests: Conflict-of-interest disclosure: K.S.-W. is on advisory committees for Pfizer, Global Blood Therapeutics (no honoraria), and Celgene (honorarium); has provided nonpaid expert testimony; and is a Sickle Cell Disease Association of America, Inc. Board Member., (© 2019 by The American Society of Hematology. All rights reserved.)

Background: Alloanti-M was once regarded as not clinically significant, with a few exceptions in extremely rare cases. However, an increasing number of cases of severe hemolytic disease of the fetus and newborn (HDFN), resulting in fetal hydrops and recurrent abortion caused by alloanti-M, have been reported mainly in the Asian population., Study Design and Methods: Three pregnant Chinese women with a history of abnormal pregnancy with hydrops fetalis were encountered. During this pregnancy, a series of clinical examinations and an alloantibody identification against RBCs and platelets were conducted. Intrauterine transfusion and postnatal transfusion were then performed in the fetuses. In addition, the HDFN cases caused by alloanti-M reported in different ethnic groups as well as their clinical and serologic features are also summarized., Results: Three pregnant women were identified with an M-N+ phenotype and IgM mixed with IgG alloanti-M in serum. Their fetuses were found by ultrasound examination and cord blood testing to have severe anemia. Additionally, an M+N+ phenotype and IgG alloanti-M were detected in the cord blood of the three fetuses with titers ranging from 1:1 to 1:128. Moreover, low reticulocyte counts and negative direct antiglobulin tests were also shown in two of the fetuses. After receiving intrauterine transfusions and postnatal transfusions several times, these three fetuses eventually survived and then healthfully developed in the follow-up tracking., Conclusion: Alloanti-M immunization can cause severe HDFN with hyporegenerative anemia, often seen in the Asian population, and suppression of erythropoiesis might account for it., (© 2018 AABB.)

Common causes of fetal anemia and hydrops include parvovirus B19 infection during the first 2 trimesters of pregnancy, as well as maternal alloimmunization to RhD with subsequent hemolytic disease of the fetus and newborn (HDFN) in an RhD positive fetus. Although both of these conditions have historically caused significant fetal morbidity and mortality, the advent of intrauterine transfusion (IUT) over the last few decades has dramatically improved outcomes. Prior literature has extensively documented placental changes associated with untreated parvovirus infection and RhD HDFN in intrauterine fetal demises and preterm births; however, histopathologic changes in term placentas from term infants treated with IUT have not been reported. We present placental findings in 2 cases of parvovirus B19-associated hydrops and 2 cases of RhD HDFN-associated hydrops in term infants after IUT, highlighting unique aspects that may be diagnostically useful for the examining pathologist.

Purpose of Review: This review aims to highlight recent advances in our understanding of how anti-red blood cell (RBC) antibodies prevent erythrocyte immunization with an emphasis on new murine models., Recent Findings: New murine models with clinically relevant human erythrocyte antigens have been used to understand the alloimmunization process and its inhibition. The search to elucidate the mechanism of action of IgG-mediated inhibition of erythrocyte alloimmunization has provided new evidence in support of a potential role for epitope masking, immune deviation and/or antigen modulation in this process. In addition, recent evidence suggests that blends of monoclonal antibodies targeting nonoverlapping epitopes on the RBC surface can improve the efficacy of monoclonal antibodies approaching that of polyclonal IgG., Summary: Animal models with defined alloantigens have helped to identify important mechanistic components that lead to alloimmunization and its inhibition by IgG. A better understanding of the underlying mechanisms leading to hemolytic disease of the fetus and newborn is required to develop the most effective prevention strategies for future patients.

Background: Individuals with the partial D phenotype when exposed to D+ red blood cells (RBCs) carrying the epitopes they lack may develop anti-D specific for the missing epitopes. DNB is the most common partial D in Caucasians and the clinical significance for anti-D in these individuals is unknown., Study Design and Methods: This article describes the serologic genotyping results and clinical manifestations in two group D+ babies of a mother presenting as group O, D+ with alloanti-D., Results: The mother was hemizygous for RHD*DNB gene and sequencing confirmed a single-nucleotide change at c.1063G>A. One baby (group A, D+) displayed bilirubinemia at birth with a normal hemoglobin level. Anti-A and anti-D were eluted from the RBCs. For the next ongoing pregnancy, the anti-D titer increased from 32 to 256. On delivery the baby typed group O and anti-D was eluted from the RBCs. This baby at birth exhibited anemia, reticulocytosis, and hyperbilirubinemia requiring intensive phototherapy treatment from Day 0 to Day 9 after birth and was discharged on Day 13. Intravenous immunoglobulin was also administered. Both babies were heterozygous for RHD and RHD*DNB., Conclusion: The anti-D produced by this woman with partial D DNB resulted in a case of hemolytic disease of the fetus and newborn (HDFN) requiring intensive treatment in the perinatal period. Anti-D formed by women with the partial D DNB phenotype has the potential to cause HDFN where the fetus is D+. Women carrying RHD*DNB should be offered appropriate prophylactic anti-D and be transfused with D- RBCs if not already alloimmunized., (© 2017 AABB.)

Associations between blood type and disease have been studied since the early 1900s when researchers determined that antibodies and antigens are inherited. In the 1950s, the chemical identification of the carbohydrate structure of surface antigens led to the understanding of biosynthetic pathways. The blood type is defined by oligosaccharide structures, which are specific to the antigens, thus, blood group antigens are secondary gene products, while the primary gene products are various glycosyltransferase enzymes that attach the sugar molecules to the oligosaccharide chain. Blood group antigens are found on red blood cells, platelets, leukocytes, plasma proteins, certain tissues, and various cell surface enzymes, and also exist in soluble form in body secretions such as breast milk, seminal fluid, saliva, sweat, gastric secretions, urine, and amniotic fluid. Recent advances in technology, biochemistry, and genetics have clarified the functional classifications of human blood group antigens, the structure of the A, B, H, and Lewis determinants and the enzymes that produce them, and the association of blood group antigens with disease risks. Further research to identify differences in the biochemical composition of blood group antigens, and the relationship to risks for disease, can be important for the identification of targets for the development of nutritional intervention strategies, or the identification of druggable targets. WIREs Syst Biol Med 2016, 8:517-535. doi: 10.1002/wsbm.1355 For further resources related to this article, please visit the WIREs website., Competing Interests: None., (© 2016 Wiley Periodicals, Inc.)

Twin anemia-polycythemia sequence (TAPS) is a group of disorders in monochorionic twins characterized by a large intertwin hemoglobin difference without amniotic fluid discordance. Reticulocyte count is used to diagnose this condition, but little is known about the role of erythroblasts, which are the prior stage of reticulocytes. In the present case of TAPS, the 25-yr-old Japanese mother showed no signs of oligohydramnios or polyhydramnios throughout gestation. The twins were born at 36 weeks and 6 days, weighing 2,648g and 1,994g. The intertwin hemoglobin difference in umbilical cord blood was (21.1－5.0＝) 16.1g/dL and the donor twin showed signs of chronic anemia, including myocardial hypertrophy and pericardial effusion. Erythroblastosis of the donor twin was prolonged (53,088.5, 42,114.8 and 44,217.9/μL on days 0, 1 and 2, respectively). Erythroblastosis, which indicates chronic anemia, is also a good diagnostic indicator of TAPS.

Background: Neonatal blueberry muffin lesions are rare cutaneous eruptions, presenting as transient, non-blanching, red-violaceous papules, mostly localized in the trunk, head and neck, attributable to a marked dermal hematopoietic activity. Congenital infections of the TORCH complex (toxoplasmosis, other, rubella, cytomegalovirus and herpes) and hematological disorders have been classically associated with this neonatal dermatological manifestation. We report for the first time an unusual presentation of blueberry muffin lesions in a neonate born from a mother affected by severe anemia during pregnancy., Case Presentation: A male, white Caucasian, neonate showed a cutaneous rash at birth, suggestive of "blueberry muffin"-like lesions. These cutaneous lesions were associated with marked elevation of the circulating nucleated red blood cells, and with ultrasound findings of peculiar brain ischemic porencephalic lesions. The clinical features of spontaneous disappearance and the association with marked erythroblastosis strongly suggest that these dermatological findings may be the consequence of an extramedullary hematopoiesis unexpectedly evoked by the intrauterine chronic exposure to hypoxia caused by severe maternal anemia., Conclusions: In conclusion, fetal hypoxia secondary to severe maternal anemia may play a causative and unreported role in the development of neonatal blueberry muffin lesions.

Hemolytic disease of the newborn (HDN) arising from MNSs incompatibility is rare, with few reports of prolonged anemia and reticulocytopenia following HDN. We report the younger of 2 male siblings, both of whom had anti-M-induced HDN and anemia persisting for over a month. Peripheral reticulocytes remained inappropriately low for the degree of anemia, and they needed multiple red cell transfusions. Viral infections were ruled out. Corticosteroids were given for suspected pure red cell aplasia. Anemia and reticulocytopenia subsequently improved. Colony-forming unit erythroid assay revealed erythropoietic suppression of M antigen-positive erythroid precursor cells cultured with maternal or infant sera containing anti-M. In conclusion, maternal anti-M caused HDN and prolonged anemia by erythropoietic suppression in 2 siblings.

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., (© International & American Associations for Dental Research 2015.)

Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema, ascites, heart failure, and death. Infants affected with HDFN can have hyperbilirubinemia in the acute phase and hyporegenerative anemia for weeks to months after birth. The diagnosis and management of pregnant women with HDFN is based on laboratory and radiographic monitoring. Fetuses with marked anemia may require intervention with intrauterine transfusion. HDFN due to RhD can be prevented by RhIg administration. Prevention for other causal blood group specificities is less studied., (© 2015 by The American Society of Hematology. All rights reserved.)

Maternal red-cell alloimmunization occurs when a woman's immune system is sensitized to foreign red-blood cell surface antigens, leading to the production of alloantibodies. The resulting antibodies often cross the placenta during pregnancies in sensitized women and, if the fetus is positive for red-blood-cell surface antigens, this will lead to hemolysis of fetal red-blood cells and anemia. The most severe cases of hemolytic disease in the fetus and newborn baby are caused by anti-D, anti-c, anti-E and anti-K antibodies. There are limited data available on immunization rates in pregnant women from Turkey. The aim of the present study was to provide data on the frequency and nature of maternal RBC alloimmunization in pregnant women in a tertiary care hospital. In this study, we retrospectively evaluated the indirect antiglobulin test results of Rh-negative pregnant women performed in our Blood Bank between 2006 and 2012. Indirect antiglobulin test positive women also underwent confirmatory antibody screening and identification. During the study period, 4840 women admitted to our antenatal clinics. With regards to the major blood group systems (ABO and Rh), the most common phenotype was O positive (38.67%). There were 4097 D-antigen-positive women (84.65%) and 743 women with D-antigen-negative phenotype (15.35%). The prevalence of alloimmunization was found to be 8.74% in D-antigen negative group. Despite prophylactic use of Rh immunglobulins, anti-D is still a common antibody identified as the major cause of alloimmunization in our study (anti-D antibody 68.57%, non-D antibody 31.42%). While alloimmunization rate to D antigen was 6.46%, non-D alloimmunization rate was 2.69% among Rh-negative pregnant women. Moreover, detailed identification facilities for antibodies other than anti-D are not available in most of centers across Turkey. However, large-scale studies on pregnant women need to be done in order to collect sufficient evidence to formulate guidelines and to define indications for alloantibody screening and identification., (Copyright © 2013. Published by Elsevier Ltd.)

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., (Copyright (c) 2009 S. Karger AG, Basel.)

The authors present a case of stillbirth in which histologic examination of the placenta provides the opportunity to make a definitive diagnosis of a death due to fetal thrombotic vasculopathy (FTV). Establishing the etiology in cases of stillbirth may avoid medical malpractice litigation. The better knowledge of the cause of stillbirths also helped obstetricians to recognize factors that could have prejudiced future pregnancies.

The Lutheran blood group system consists of 19 antigens: four pairs of antithetical antigens--Lu(a)/Lu(b), Lu6/Lu9, Lu8/Lu14, and Au(a)/Au(b)--and 11 antigens of very high frequency. These antigens are located on four of the five immunoglobulin-like domains of both isoforms of the Lutheran glycoprotein. The LU gene is on chromosome 19 and comprises 15 exons. The two glycoprotein isoforms differ in the length of their cytoplasmic tails as a result of alternative splicing of intron 13. Lu(null) phenotype arises from homozygosity for inactivating mutations in the LU gene.The dominantly inherited Lu(mod) phenotype, In(Lu), results from heterozygosity for inactivating mutations in KLF1, the gene for the erythroid transcription binding factor EKLF. Clinically, antibodies of the Lutheran system are relatively benign. When hemolytic, they generally cause only mild, delayed hemolytic transfusion reactions or hemolytic disease of the fetus and newborn that can be treated by phototherapy. The Lutheran glycoproteins, which are members of the immunoglobulin superfamily of adhesion molecules and receptors, bind isoforms of laminin with alpha5 chains,components of the extracellular matrix abundant in vascular endothelia. The primary function of the Lutheran glycoproteins on RBCs could involve the transfer of maturing RBCs from the bone marrow to the peripheral circulation. They could also be involved in vascular occlusion and thrombotic events as complications of sickle cell disease and polycythemia vera, respectively.

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.

Objective: This study was undertaken to audit ultrasonographic measurements of fetal liver length and middle cerebral artery peak velocity in cases of red blood cell alloimmunization between 1986 and 1999., Study Design: A total of 200 fetuses at risk for anemia because of red blood cell alloimmunization underwent ultrasonographic measurement of the length of the right lobe of the liver, 45 underwent Doppler recording of middle cerebral artery peak velocity, and 119 underwent fetal blood sampling., Results: The overall survival was 188 of 200 (94%). Among 69 fetuses found to have anemia, liver length values in 64 (93%) were at the 95th percentile or greater, and the other 5 were in the upper part of the normal range. The middle cerebral artery peak velocity was > or =95th percentile in 15 of the 19 cases of anemia in which this value was measured (79%). Among those measured within 1 week of birth, all liver lengths were at least in the upper part of the normal range, with most >95th percentile, including 1 case with a cord blood hemoglobin concentration <90 g/L., Conclusions: All fetuses with anemia identified at fetal blood sampling had enlarged livers with 93% at > or =95th percentile. The peak velocity in the middle cerebral artery was abnormal in most fetuses with anemia.

Fetal anemia causes hydrops fetalis and fetal ascites/hydrothorax, and in severe cases the prognosis is poor. Little other than alloimmunity and viral infections are known as mechanisms causing fetal anemia. The aim of this study was to elucidate any pathogenesis in fetal anemia due to otherwise idiopathic etiology. The levels of three hematopoietic cytokines, IL-3, erythropoietin (EPO), and granulocyte colony-stimulating factor (G-CSF) were measured in blood samples obtained by cordocentesis from six fetuses with anemia (Hb <10.0 g/dl) and 34 fetuses without anemia. Cordocentesis was performed prior to the onset of labor or uterine contractions in all pregnant women. The concentration of IL-3 in fetuses with anemia [M+/-(SD), 8.3 (10.1) pg/ml] was significantly lower than that in fetuses without anemia [59.9 (71.0) pg/ml]. EPO and G-CSF levels were not different between the two groups. In addition, through in vitro colony formation assay, using blood stem cells from two fetuses with severe anemia and three fetuses without anemia, it was found that colony forming unit-erythroid, burst forming unit-erythroid and granulocyte macrophage-colony forming unit were significantly suppressed in blood stem cells from the two fetuses with severe anemia. Thus, the malfunction of differentiation and proliferation of blood stem cells and the decrease of hematopoietic cytokine levels in the fetal circulation may be responsible for the occurrence of fetal anemia.

Data in the literature and author's research regarding the role of the immune reaction of fetuses and newborns in the pathogenesis of RhD conflict and hemolytic disease of newborns was analyzed. In this disease, the immune response of fetuses and newborns is shown to develop under the effects of maternal antigens, including RhD IgG, which cross the placenta. One of the results is the formation of immune complexes (ICs) between the maternal antigens and fetal IgM. In the intensive immune reaction, these ICs are removed from the infants at a high rate. As a result, the intensity of erythrocyte destruction, the degree of anemia and hyperbilirubinemia decrease. Various forms of HDN are of different intrauterine duration: from a few days in the icteric form without anemia to a month or more, in the hydropic form. In the latter form, decompensation of the immune system develops; extravascular erythroclasia by macrophages is replaced by intravascular lysis of erythrocytes. We suggest some methods to determine the fetal condition and a cure for the most severe cases of HDN, as well as a way of decreasing RhD-sensitization in women. These suggestions may be of interest to specialists in pediatrics and obstetrics and may be of clinical use.

This study reports the Hb, erythropoietin (Epo), and reticulocyte course at different postnatal ages (range, 8-83 d) of 56 blood samples from 30 newborns (range, one or two blood samples from each newborn) with erythroblastosis fetalis (18 intrauterine transfused (IUTd) and 12 non-IUTd). Hb, Epo, and reticulocyte values were not statistically different in IUTd and non-IUTd cases. As age increased, decreasing Hb values and increasing Epo levels were observed. The reticulocyte count was relatively low in all but six cases. There was an inverse correlation between Epo and Hb (r = -55, p < 0.001), but no correlation was found between Hb and reticulocytes or between Epo and reticulocytes. When groups were formed on the basis of Hb levels, anemic newborns showed higher serum Epo than did nonanemic patients (p < 0.02). In the present study we found a significant increase in Epo levels in anemic newborns without a rise in the reticulocyte count. These results suggest that other mechanisms, rather than low Epo production, could be involved in the pathogenesis of this anemia. Persisting anti-D antibodies, probably at a medullary level, may destroy erythrocyte precusors, leading to anemia with a low reticulocyte count.

Although Rh alloimmunization has been successfully reduced in frequency and severity since the implementation of Rh immune globulin, cases still occur. The management of affected pregnancies requires the efforts of a team which includes obstetrics/fetal medicine, the blood transfusion service, haematological support, nursing assistance and neonatology. The aim of antenatal management is to predict whether or not the fetus is severely affected, to correct the fetal anaemia and to deliver the baby at the optimal time. The management has improved markedly with the introduction of high-resolution real-time ultrasound, fetal blood sampling, intravascular fetal blood transfusion and/or intraperitoneal transfusion and meticulous fetal surveillance. With appropriate and timely management in severely alloimmunized patient, the survival rate of affected fetuses in some centres is now about 90%. There is still a need for research into new methods of treatment such as high dose intravenous immunoglobulin, which might non-invasively diminish fetal red cell destruction. Due to the reduced frequency of severe disease, regionalized treatment centres are essential in order to maximize the experience and efficiency of the management teams.

Placental pathology is rarely a part of the training for either obstetrician or pathologist. As a result there has been confusion regarding the potential benefits of routine placental examination. These benefits include clarification of the causes of many adverse pregnancy outcomes, improvement of the risk assessment for future pregnancies, and ascertainment of newborn risk for long-term neurodevelopment sequelae. Information on placental abnormalities may reveal the presence of chronic fetal insults and allow their differentiation from acute (peripartum) stresses. Current methods of risk assessment fail to identify the majority of pregnancies that end in prematurity, stillbirth, growth retardation, or fetal distress. We suggest that placental pathology should be a routine component of obstetric-neonatal care.

In this chapter, placental development, morphology, and indications for its examination have been reviewed. Techniques for placental examination with practical suggestions applicable to the surgical pathology laboratory have been pointed out. Several specific examples of clinical conditions in which morphologic alterations within the placenta assist with or establish a diagnosis have been presented. It is hoped that this information will encourage pathologists to use this important organ more fully as a resource in diagnoses and patient care.

An outbreak of acute hemolytic disease in a large flock of sheep resulted in a mortality of approximately 5% in lambs. A diagnosis of Leptospira interrogans serotype hardjo infection was established on the basis of the presence of leptospires in the urine of one lamb, serologic findings in a guinea pig inoculated with this urine, L. hardjo titers in lambs, and pathologic findings. Prominent necropsy findings included severe icterus, thin watery blood, dark red to black kidneys and severe hemoglobinuria.

I have reviewed hemolytic disease of the newborn to discuss with you the mechanisms by which red cell destruction occurs in the newborn and how such a process may be detected. I have introduced the concept of "minimal hemolytic disease" that manifests in ABO incompatibility disease and have suggested that this process may contribute significantly to the problem of idiopathic hyperbilirubinemia. There are many potential causes for this condition and they deserve study. The diagnosis of hemolytic disease in the newborn includes careful assessment of anemia and of all the factors unique to the newborn that affect its appearance and interpretation, as well as careful assessment of the erythrocytes themselves.

A vasodestructive process has been identified within the placenta, which focuses on the entire placental vascular tree. Its presence is correlated with significant fetal mortality; liveborn infants are growth retarded and frequently in distress. Characteristic morphologic features have been identified in chorionic vessels of all sizes and these explicit pathologic changes are repetitive from case to case. Associated events suggest that hemorrhagic endovasculitis of the placenta is a clinicopathologic entity having maximal impact on pregnancies of affected patients. A number of accompanying pathologic and clinical features would suggest an infectious association or cause. There are several known categories of disease which manifest similarity to this placental alteration. These include microangiopathic hemolytic anemia, several postinfectious states, several known types of vasculitis, and AIDS. Long-term studies to gain further insight into this pathologic event are currently underway at the Michigan Placental Tissue Registry. These studies include: an epidemiologic field investigation with followup on growth and development of liveborn infants; data collection and analysis with respect to recurrence, geographic distribution, and the clinical course of affected pregnancies. An indepth pathologic analysis is ongoing including ultrastructural and immunopathologic studies on affected and control placentas. Appropriate microbiologic and serologic studies are planned with reference to the infectious aspects of this entity we have described. It is hoped that increasing awareness of this pathologic process within the placenta, particularly by pathologists, will contribute to our understanding of events which are deleterious to intrauterine growth and survival.

Intrauterine intravascular transfusion for the treatment of severe erythroblastosis fetalis has resulted in a number of benefits: (a) Direct access to the fetal vasculature allows an accurate assessment and prompt correction of anemia, albeit temporary. In contrast, intraperitoneally transfused blood may be absorbed erratically, especially in the face of ascites. (b) Intravascular treatments can be performed, in general, as early as 17 weeks of gestation, earlier than intraperitoneal approaches permit. (c) Reversal of hydrops along with the correction of anemia and hypoproteinemia has significantly reduced neonatal morbidity and mortality. None of the surviving neonates in our series required either thoracentesis or paracentesis following delivery, and 40% did not require neonatal exchange transfusion. (d) Treatments may be safely performed until pulmonic maturity has been established and/or an EFW of greater than 2,000 g has been reached, reducing problems of prematurity. (e) Central vein and umbilical vein hypertension may be arrested or prevented, thereby allowing fetal liver function to return to normal. While isoimmunization stands as a disease that has been quite successfully reduced in frequency and severity by the careful attention and treatment by obstetricians, cases still occur. Due to the reduced frequency of severe disease, fewer physicians are trained and experienced in performing this difficult procedure. As fewer transfusions are required, the value of regionalized treatment centers will have to be considered carefully, in order to maximize the experience and efficiency of the intravascular intrauterine transfusion treatment teams.

Autopsies were performed in 40 cases of nonimmune hydrops fetalis during the period from 1975 to 1983. In 25 cases specific anatomic diagnoses, including hematologic disorders, infections, chromosomal abnormalities, congenital anomalies, and tumors, were made. In the majority the diagnosis of hydrops fetalis was made prenatally by ultrasonography. The mean gestational age at delivery was 30 weeks; 23 infants were stillborn, and 17 died during the neonatal period. Body weights were consistently increased; peripheral edema and ascites were present in all cases and pleural effusions in all but two cases. Hepatosplenomegaly, cardiomegaly, and pulmonary hypoplasia were frequent findings. The most consistent microscopic changes involved endocrine organs. Islet cell hyperplasia and Leydig cell hyperplasia were common, and thyroid hyperplasia was found occasionally. The fetal zone of the adrenal cortex was often thick and composed of swollen, vacuolated cells. Enhanced extramedullary erythropoiesis was observed in all cases. Thirty-nine placentas were examined; 34 were edematous (mean weight, 547 g), with villous edema, excess erythroblastemia and normoblastemia, and occasional intravillous hematopoiesis. Nonimmune hydrops fetalis has a range of known causes. Thorough autopsy, including placental examination, is the most useful approach for determining the etiology. In 23 cases the probable or possible cause was established in this manner. Antibody studies should also be performed in all cases to exclude an immunologic etiology. Synthesis of clinical, serologic, and pathologic data offers prospects for rational management and prediction of recurrence.

Human amniotic epithelium from patients with normal pregnancy (normal amniotic epithelium) and from patients with materno-fetal rhesus incompatibility has been examined under the light and electron microscope. In comparison with normal amniotic epithelium, the epithelium in rhesus incompatibility displays the following morphological changes: 1. Unequal distribution and variable shape of the plump microvilli 2. Considerable narrowing of the intercellular spaces 3. Vacuolization of the cytoplasm 4. Absence of glycogen granules 5. Thickening of the basal membrane. There is a direct correlation between the morphological changes in the amniotic epithelium and the severity of the disease. Since rhesus factors are present only in erythrocytes, it is probably that these changes are not based on a direct immune conflict. On the contrary, they are more likely due to fetal hypoxia and to the cytotoxic effect of unbound, unconjugated bilirubin in the amniotic fluid.

Pancreatic sections from 21 cases of rhesus disease and 20 control newborn infants of 30--40-wk gestational age were stained by the immunoperoxidase method for insulin, glucagon, somatostatin, and pancreatic polypeptide (PP). The fractional area occupied by each cell type was estimated, taking note of whether the gland contained PP-rich (ventral lobe) or PP-poor islets (dorsal lobe). In the PP-rich part of the pancreas, the volume fraction of all four endocrine cell types was significantly greater in the rhesus cases than in the controls. No difference was found between the two groups in the PP-poor part of the gland. The results show that abnormal development of the PP-rich part of the pancreas occurs in erythroblastosis fetalis. The localization of the changes to one part of the pancreas may explain some of the earlier conflicting reports on this topic.

Ten cases of hydrops fetalis not associated with serologic incompatibility between mother and infant were studied by autopsy. Classic trisomy 21 was present in two, and in six others the postmortem examination revealed major congenital abnormalities (hydrometrocolpos-polydactyly syndrome, achondrogenesis type 2, congenital adenomatoid malformation of the lung, and aortic valvular dysplasia with left ventricular endocardial fibroelastosis). In two instances, anasarca was associated with a congenital tumor: a sacrococcygeal teratoma and an adrenal neuroblastoma. In six fetuses, prenatal diagnosis of hydrops fetalis or severe congenital malformations was established by ultrasonography.

Anaplasma marginale infections were induced in 3 calves previously affected with neonatal immunohemolytic anemia (NIA). Similar infections were induced in 6 splenectomized and 7 intact calves. The response to infection by 3 calves (NIA recovered) closely resembled infections seen in splenectomized calves, being markedly more severe than similar infections in intact calves. Spleens from 3 (NIA recovered) calves after splenectomy were about one-tenth normal size. Marked recrudescing anaplasmal infections were not detected after splenectomy of the calves (NIA recovered), whereas marked recrudescing infections were observed after splenectomy of 2 intact calves having recovered from the primary infections.

The latex injection-corrosion cast technique coupled with scanning electron microscopy was applied to the study of severe Rh sensitization of the placenta. The main observed ultrastructural changes in fetal vasculature in this type of placenta were very similar to those of the small for gestational age placenta; large-sized vessels exhibited less branching than those of the normal placenta, and the capillary network showed numerous vascular buds and "H"-shaped anastomoses. In addition, in Rh-sensitized placentas, the capillary network was remarkably sparse, and the cast also revealed smooth-surfaced veins with distinct U shapes undulating through the placental stroma. These U-shaped veins may be the result of umbilical flow impedance with subsequent umbilical venous hypertension, which stretches the veins into undulating form.