16
Erythroblastosis Fetalis and Hydrops Fetalis
production and premature dissemination of immature red cell precursors (nucleated red blood cells, NRBCs). The hematopoietic tissue becomes increasingly activated in the fetus and the peripheral blood thus con- tains an increased number of NRBCs and erythroblasts, elegantly dem- onstrated by Nicolaides et al. (1988a,b). They performed reticulocyte counts in 127 pregnancies with isoimmunization, from 17 to 36 weeks, and also suggested that it may be the extensive hepatic red cell produc- tion that may cause the hydrops, by obstruction of sinusoidal blood flow. In our opinion, this is not the most likely mechanism for hydrops to develop. We believe that fetal cardiac failure is the main cause of hydrops and of the placental changes. The high-output congestive heart failure results from anemia and is the presumed cause of cardiomegaly and heart failure in EF (Naeye, 1967). The issue is not completely resolved, however, as there is no strict correlation between the severity of anemia and cardiac hypertrophy (Carter et al., 1990). From the frequently extensive hemolysis, large iron stores may occur in the liver and spleen, whereas the fetus becomes progressively anemic. When the hematocrit falls much below 15%, edema, ascites, and eventually anasarca develop—the condition known as hydrops fetalis (Saltzman et al., 1989). Normative values for hemoglobin and NRBC and reticu- locyte counts, ascertained by cordocentesis, are to be found in the contribution by Nicolaides et al. (1989). They discovered that hemo- globin and red blood cell counts increased linearly from 17 to 40 weeks’ gestation. Importantly, the “erythroblast count decreased expo- nentially from a mean of 83/100 leukocytes at 17 weeks to 4/100 leukocytes at 40 weeks.” Similar values obtained by other investigators were reviewed by Weiner et al. (1992), who also measured protein levels, enzymes, pH, and gases, as well as venous pressure. Thilaga- nathan and collaborators (1992) found that erythropoietin (EPO) levels were significantly increased only in severe fetal anemia. Moya and his colleagues (1993) found that EPO levels were elevated in erythroblas- tosis also, but before 24 weeks’ gestation this response was much smaller.
Fetal hydrops is now readily diagnosed sonographically (Saltzman et al., 1989); if it is due to hemolysis, the hydrops may be quickly and completely reversed when the anemic fetus is transfused intravas- cularly before birth (abdominally or by cordocentesis), thus restoring oxygenation (Socol et al., 1987; Grannum et al., 1988). The latter authors documented the impressive changes in protein and hemoglobin levels that occur. Nicolaides et al. (1988) who provided the normative values for fetal hemoglobin levels from 17 to 40 weeks’ gestation (11–15 g/dL), found that hydropic fetuses had hemoglobin values of 7 to 10 g/dL. A study investigating the possible mechanism of fetal death occurring in such pregnancies during transfusion showed that acute increases in hematocrit were associated with substantial mortality (Radunovic et al., 1992), whereas Nicolini et al. (1989) implicated
519
ERYTHROBLASTOSIS FETALIS
Erythroblastosis fetalis, or hemolytic disease of the newborn, is a condi- tion caused by specific antibodies of the mother, directed against red cell antigens of the fetus. These are largely Rh–(D) antigens, but rare cases of sensitization against other antigens (e.g., Kell), and of ABO incompatibility with fetal hemolytic disease have been described.
Leventhal and Wolf (1956) have presented Kell-isoimmunization as a cause of fatal erythroblastosis fetalis (EF). This was also found in the well-illustrated case of Ivemark et al. (1959). Anti-K antibodies usually arise as a result of transfusion and the fetal disease is usually mild. Of 194 pregnancies complicated by this antibody constellation, only 16 affected babies were identified, of which three were severely affected by hemolytic disease (Leggat et al., 1991). The difficulty in this situation is the identification of the pregnancies at risk, an aspect discussed in some detail in an editorial in Lancet (1991). Anti-K hemolytic disease does not differ histopathologically from anti-D–caused erythroblastosis.
However, there may be a difference in the response to this antibody.
Vaughan et al. (1998) showed that they specifically inhibit growth of K-positive erythroid precursors and may thus lead to severe fetal anemia. Relatively few cases of typical, severe EF have been described as being due to ABO incompatibility. These were summarized by Freda and Carter (1962), and a fatal case is delineated by Miller and Petrie (1963), but usually, the hemolytic disease of ABO-incompatibility is mild. The pathologic findings of infant and placenta are the same as those in EF due to Rh incompatibility; in their case, the placenta weighed 900 g and had typical features of erythroblastosis. Other types of hemolysis occur which also produce similar pathologic features of infant and placenta. Thus, hemolysis in fetal blood may rarely result because of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, virus infection, and for other uncommon reasons. These causes of fetal hemolysis must be differentiated from the classic erythroblastosis.
As RhoGAM prophylaxis (Mittendorf & Williams, 1991) has become more widespread, the typical disease has become relatively uncommon in this country. Pathologists and clinicians are now more challenged to unravel the causes and therapy of “nonimmunologic hydrops fetalis”
(vide infra) and of other causes of prenatal anemia, such as transpla- cental bleeding (vide infra and Chapter 17). From a pathologist’s point of view, these conditions are often indistinguishable, and additional tests need to be employed to identify the many specific disease entities that comprise this complex fetal condition. It is worth mentioning that the fetal genotype (RhD+) is now commonly made in Europe from free DNA in maternal serum (Gautier et al. 2005).
The cause of typical erythroblastosis is the transplacental transfer of maternal antibodies that cause hemolysis in the fetus. As a conse- quence, the fetus attempts to repair this loss of red blood cells by over-
increases in venous pressure during transfusion. The bilirubin, liberated by hemolysis, is effectively exchanged transplacentally and the neonate rarely has much jaundice. This is a later, usually neonatal development in erythroblastosis.
Other fetal changes are worth mentioning. Hepatosplenomegaly is prominent; usually the infants have some hypoproteinemia. They also often suffer severe thrombocytopenia (Harman et al., 1988) and display increased beta-cell activity of their islets of Langerhans. The islet cell hyperplasia, which is combined with a greater islet insulin content (Driscoll & Steinke, 1967), was explained to result from insulin binding by the circulating hemoglobin (Steinke et al., 1967). The occasional presence of large maternal ovarian lutein cysts with hydrops fetalis is more difficult to explain. These cysts are clearly associated with an usually enlarged placenta, as was shown by Burger (1947), Christie (1961), Rabinowitz et al. (1961), and Hatjis (1985). Ovarian lutein cysts are also found in nonimmune hydrops, and they occasionally accompany fetal triploidy as well. These varied observations have led to the suggestion that, similar to the ovaries of women with hydatidiform moles, the fetal ovarian cysts result from elevated titers of human chori- onic gonadotropin (hCG), produced because of the enlargement of the placentas with increased trophoblastic mass. Christie (1961) and Hatjis (1985) have determined that the maternal serum levels of hCG are significantly above normal with fetal hydrops. Initially, this elevation of hCG titers was thought to result from the persistent presence of the Langhans layer of trophoblast, or from its exaggerated appearance.
Now that the origin of hCG has clearly been determined to be the syncytium, the abundance of hCG with fetal hydrops must be assumed to result from placental enlargement alone. In this connection, it is rele- vant to point out that human placental lactogen (hPL) and placental protein 5 (PP5) are also elevated in fetal hydrops (Lee et al., 1984).
Although the elevation of hPL and hCG levels may relate to a larger placental mass, as suggested by Lee et al. (1984), the increase of PP5 levels is not so readily understood.
Placental Pathology in Erythroblastosis
The striking features of the placenta in erythroblastosis fetalis are its pallor, uniform enlargement, presence of bone marrow elements in the fetal circulation, and the villous “immaturity” (Fig. 16.1). Because of the edema and enlargement, placentas of erythroblastosis are also
very friable. The changes were delineated early by Hellman and Hertig (1937), prior to a knowledge of the nature of the disease. They enumerated syncytial degen- eration, persistence of Langhans’ layer, prominence of Hofbauer cells, presence of erythropoietic cells in the vascular spaces, and stromal edema of villi. Since then, many studies have been conducted, all with essentially the same findings. Of comparative interest is that the hematopoiesis proceeds within the villous blood vessels (Alenghat & Esterly, 1983), in contrast to the villous arrangement in marmoset monkeys where it also pro- ceeds in the villous stroma. It is now apparent that the placental alterations are largely secondary to the fetal anemia and to cardiac failure. Wentworth (1967) studied the placentas with the Gough large-section technique and affirmed that “the more severely the baby was affected, the larger the placenta was in relation to the baby.” In the severe cases, the placentas were extremely pale and more friable than normal. Additional diagnostic histologic fea- tures in the placenta were a marked decrease in the number of fetal vessels and an increase in the number of NRBC in these vessels. Langhans’ layer persisted in all cases but in itself it was not considered to be a specific change. Wentworth believed that the pathologic changes resulted from a direct effect of antibodies on the pla- centa. Montemagno et al. (1966) suggested from immu- nofluorescent antibody studies, that the syncytium possesses the Rh antigen and that antibodies localize to these antigens. Thus, the antibodies were believed to damage the syncytium and thereby produce the patho- logic changes seen in the placenta of EF. More detailed examination of this question by Benachi et al. (1998), however, revealed decisively that the RhD antigen is not expressed by syncytiotrophoblast.
On occasion, one may find small amounts of hemosid- erin deposited in chorionic macrophages betraying the long-standing hemolysis. It is not a prominent finding,
Figure 16.1. Villus in stillborn with typical erythroblasto- sis fetalis showing edema, abundance of Hofbauer cells, and persistent cytotrophoblast. Because of fetal demise, the fetal vessels are obliterated. H&E ¥250.
however. We presume that the affinity for iron of fetuses is too great for substantial hemosiderin accumulation to take place in the placenta. Rarely, one observes some icteric staining of placental surface vessels and umbilical cord. We now know that these are nonspecific changes that are essentially similar in placentas of unrelated types of hydrops fetalis (e.g., a-thalassemia). We believe that it is impossible, without history or specific immunologic tests, to make the specific diagnosis of EF from a placen- tal examination alone, an opinion similar to that expressed by Bouissou et al. (1969), who suggested, however, that the crowding of hematopoietic elements in the hepatic parenchyma may cause the fetal edema, which is contrary to our views. It is noteworthy that with the polymerase chain reaction (PCR) to ascertain fetal Rh genotype, the diagnosis is now readily achieved from blood and by the usage of amnionic fluid (Veyer & Moise, 1996; Veyer et al., 1996). The possible importance of vascular endothe- lial growth factor (VEGF) distribution in the placenta was investigated by Shiraishi et al. (1997). Because Rh disease is uncommon in Japan, they studied primarily the placentas of nonimmune hydrops by immunohistochem- istry of this placentally active cytokine (Jackson et al., 1994). VEGF was found in syncytiotrophoblast of all placentas and in stromal cells (fibroblasts) during the first trimester of normal placentas, but not later. In the hydropic organs, however, stromal cells remained posi- tive in 12 of 18 cases, those whose outcome was poor.
They confirmed also that hydropic placentas are com- posed of hypovascular villi and made reference to the persistence of b-hCG, lactogen, and phosphatase expres- sion throughout pregnancy in hydrops fetalis (Kamat et al., 1989). Their suggestion is that, functionally as well as structurally, hydropic placentas remain immature and that VEGF may have a regulatory function in the vascu- logenesis of these abnormal placentas.
Wentworth (1967) provided an excellent photograph of the anemic and normal placental portions of a set of dizygotic (DZ) twins in which only one twin was affected.
Becker and Bleyl (1961) performed fluorescence micros- copy on such placentas and believed that these demon- strated the increased permeability of the erythroblastotic placentas. The authors showed a “condensation of . . . the interfibrillary substance of the connective tissue” of villi and believed it to be due to an increase in interfibrillary substance. This, we believe is largely the result of edema and of the accumulation of Hofbauer cells. It has occa- sionally been suggested that extramedullary hematopoi- esis also takes place within the villous stroma. We believe that this is not the case. To be sure, the abundance of erythroblasts in some cases so much crowds the fetal capillaries that a villous production site is simulated.
There is normally a large number of bone marrow–like elements in the fetal capillaries in EF; Alenghat and Esterly (1983) even found some of these cells to contain
mitoses in abortions specimens. Burstein and Blumenthal (1962) found that the abundance of syncytial knots was about the same as that found in normal controls but that the villi were much expanded; by their method, this resulted in a decreased villus count. They also empha- sized the occurrence of fetal capillary proliferative lesions.
There was no mention as to whether any of the placentas came from stillborn infants. Apparently similar patho- logic findings were presented in a Russian article that was not accessible to us (Iakovtsova, 1964). Busch and Vogel (1972) provided a complete review of the historical aspects “of the placental changes theretofore described”
and added their own observations of 58 cases. They found that these related to the severity of the hemolytic disease, that is, the degree of anemia, and emphasized the occur- rence of “maturational changes of villi.” Finally, they found that about one third of their cases had intervillous thrombi. This is indeed a common lesion in the placentas of erythroblastosis fetalis, and it is not easily or satisfac- torily explained. One may postulate that intervillous thrombi are the sequel of an increased hydrostatic pres- sure within the fetal capillaries, and resultant bleeding.
This would be supported by finding many nucleated red blood cells within the thrombi (Fig. 16.2). Intervillous thrombi, however, are also extremely frequent in hyda- tidiform moles that have no fetal vasculature. We believe that the mechanism of the formation of intervillous thromboses in both conditions may be similar. The villous edema so alters the intervillous blood flow as to cause local eddying and stasis, with thrombosis being the end result. Nevertheless, because NRBC are often found in the thrombi, fetal bleeding must occur at times. It may result from local villous hypoxic injury, as it has been repeatedly demonstrated that distention of fetal vessels and necrosis at the surface of the villi take place. This is further discussed in Chapter 17 in considerations of fetal hemorrhage. Busch and Vogel (1972) contended that the placental enlargement was the result of real growth.
The investigations by Vidyasagar and Haworth (1973), however, negated this explanation. They found no differ- ences when they compared the weights of non-EF pla- centas with those from nonhydropic cases of EF. Their decidual surfaces, and DNA, water, and protein contents all were similar.
An electron microscopic study of the placentas from erythroblastotic infants was undertaken by Jones and Fox (1978). These investigators found characteristic syncytial necrosis, cytotrophoblastic hyperplasia, thickening of basement membranes of villi and vessels, and immature endothelial cells. They did not identify a distinct patho- genesis of these alterations, but ruled out immunologi- cally mediated changes. Rather, they felt that the syncytial degeneration was the result of villous enlargement with consequent decrease of the intervillous space. The most detailed study of villous alterations in EF comes from the
Placental Pathology in Erythroblastosis 521
investigations by Pilz et al. (1980). They insisted that, in order to obtain reproducible results, it is necessary for protocols to provide specific fixation and other data. They obtained their material from in situ aspiration biopsies of eight cases of EF, and compared them with 20 normal organs. Their morphometry showed an enlargement of intermediate villi that depended upon the severity of the disease. They also observed an increase in cytotropho- blast; the terminal villi were not altered, and there was an increase in Hofbauer cells. These investigators believed that the increased number and size of Hofbauer cells probably related to the increased antigen-antibody reac- tion that must take place in the stroma of villi. They were unable to find the alterations in capillary lumens that were suggested to exist by other authors. There was no chorangiosis. They further emphasized that the changes that they observed may represent a true maturational disturbance of the villi. In this regard, it is noteworthy that calcifications of the placenta are very uncommon in EF.
Modern management of the isoimmunized gravida requires supervision of fetal progress. This includes sonography for the detection of edema, evaluation of amnionic bilirubin concentration, and the ascertainment of umbilical vein diameter. When these parameters were correlated, Reece et al. (1988) showed that umbilical venous dimension does not parallel the other time- honored methods of prenatal evaluation. Prenatal intraabdominal transfusion for the therapy of affected fetuses (e.g., Queenan & Douglas, 1965) is gradually being displaced by intravascular transfusion with cordo- centesis. This is usually done near the site of cord in - sertion on the placental surface (Rodeck et al., 1984;
Schumacher & Moise, 1996), a technique that allows sam- pling of fetal blood and estimation of total blood volume (Macgregor et al., 1988). The survival of transfused blood in the fetus is approximately similar with the two tech- niques (Pattison & Roberts, 1989; Van Kamp et al., 2005).
With the introduction of transfusion by cordocentesis, newly observed pathologic features have been witnessed in the placenta. Berkowitz et al. (1986) presented their results of 18 such transfusions, weighed the advantages and disadvantages of cordocentesis, and drew attention to the problems that ensue from the need for repeated puncture. The complications mainly involved injury to the umbilical cord; they witnessed stillbirth as a result. Pielet et al. (1988) also drew attention to the possible dangers accruing from cordocentesis. They found two stillbirths without recognizable cord injury; in another neonate with postnatal developmental delay, however, one umbilical artery was clotted after transfusion had been performed into the umbilical vein. A similar case is shown in Figure 16.3. This patient had unsuccessful cord blood sampling at 28 weeks’ gestation. At 29½ weeks successful transfu- sion of 45 mL of blood was accomplished into the vein.
At 32 weeks, another transfusion was attempted; it ended
with infusion of blood into the cord, and emergency
cesarean section was necessary. The child survived. The
cord had a superficial hematoma that extended onto the
placental surface. The entire cord was stained with hemo-
lyzed blood; hemosiderin was found in the chorionic mac-
rophages. One umbilical artery was necrotic and had old
obliterative thrombosis. Interestingly, there was a line of
polymorphonuclear leukocytic exudation extending
between the vein and the occluded artery, in the absence
of chorioamnionitis. We concluded that the degenerating
Figure 16.2. Immature placenta of live infant with edema. Marked villous vascular distention, numerous erythroblasts in the fetal circulation (left). Intervillous thrombi with nucleated red blood cells in same placenta (middle, right). H&E ¥60; ¥40; ¥160.Placental Pathology in Erythroblastosis 523
vessel caused the (sterile) inflammation. This occlusion had presumably occurred 3 weeks earlier.
Figure 16.4 shows the result of needle puncture of the fetal surface in a relevant case. During amniocentesis, the posterior-located placenta was accidentally injured, and an “upwelling” of blood was seen sonographically. Two weeks later, a stillborn fetus was delivered. The placental surface showed the site of needle injury to a surface vessel. We have also seen a stillborn fetus whose third transfusion was given into the cord. During that proce- dure, bradycardia developed after the needle was inserted.
The procedure was stopped and abdominal blood was given instead, but the fetus succumbed. There was a tense, placental portion of the cord with hematoma, and fresh occlusive thrombi were found within superficial arterial ramifications. Moreover, within this thrombotic material, typical squames were identified (Fig. 16.5), presumably introduced by the needle from the amnionic cavity. Our interpretation was that, after needle insertion, a cord hematoma and vascular spasm ensued, which were fol- lowed by arterial thrombosis. Seeds and his colleagues (1989) asserted that the demonstration of “echogenic venous turbulence” was an important feature of success- ful intravascular transfusion. When they found it absent in a case that developed bradycardia, a hematoma of the cord was found to have developed. In another case one artery thrombosed but the fetus survived. Other hemor- rhagic and thrombotic complications of cordocentesis are
Figure 16.3. Umbilical cord with thrombosis of one artery, following cordocentesis 3 weeks earlier. A new attempt caused infusion of blood into the cord substance. A line of leukocyticFigure 16.4. Mid-gestation placental surface, 2 weeks after amniocentesis. The needle injured the chorionic vessel below.
Fresh hematoma, with hemosiderin, and attempted repair of vascular wall. H&E ¥16.
exudate (arrows), coming from the umbilical vein, has formed between vein and the occluded artery, whose wall is dead.
H&E ¥3.
discussed in Chapter 12. James (1970) measured villous size in EF placentas after intrauterine (abdominal) trans- fusions had been given, and correlated the findings with hemoglobin levels. Normal values were found when the hemoglobin was above 11 g/dL, but the mean villous volume was increased in more severely affected infants.
Houston and Brown (1966) reported a case of fetal gas- bacillus infection after fetal transfusion; the edematous placenta was colonized by large numbers of gram- positive bacterial rods and there was chorioamnionitis.
When it is necessary to traverse the placenta to gain access to the fetus, it may be injured and may bleed from the villous tissue. This may then enhance maternal immu- nization. These aspects were described by Friesen et al.
(1967), who identified puncture marks in the placenta in such cases. These investigators found significant bleeding into the mother in 7.5% of cases when transgression of an anterior placenta was necessary to gain access to the amnionic sac.
As Figure 16.8 shows, the placenta of severe erythro- blastosis has a remarkable macroscopic appearance but the correct diagnosis cannot be made solely on account of the severe anemia, and the other causes of fetal anemia to be discussed subsequently need to be included in the differential diagnosis.
Twins may also be discordant (Figs. 16.6 to 16.8) or concordant for EF. When discordant, the severity of the disease often differs markedly (Beischer et al., 1969). In one such case with marked discrepancy, a difference in ABO compatibility was held to be responsible. The authors postulated that undetermined factors may be operative in producing discordance. A similarly discor- dant set of DZ twins with EF was detailed by Wiener et al. (1962). Manning et al. (1985) reported on the prenatal transfusions in a number of such twins. It is further remarkable that maternal Rh isoimmunization may occur after fetal demise. Stedman et al. (1988) described three cases. They assumed that transplacental bleeding had occurred early during this unsuccessful pregnancy, and was thus causally related to the fetal demise by the pro-
Figure 16.5. Arterial thrombus of placental surface in hydropicstillborn, days after cordocentesis for transfusion. Typical squames are seen (arrows), presumably introduced by the needle during transfusion. H&E ¥256.
Figure 16.6. Immature, fraternal twins, one with erythro- blastosis, the other normal. The placenta of the erythroblas- totic twin (Fig. 16.6) is markedly enlarged and is unusually pale.
Placental Pathology in Erythroblastosis 525
duction of antibodies. This is most likely to have been true in their first patient who had torsion of the umbilical cord; the others had negative placental findings. This observation brings into question the mechanism of primary immunization against Rh antigens, usually held to occur most frequently at the time of delivery, or imme-
diately thereafter. It is the rationale for postpartum RhoGAM prophylaxis that has been extremely effective in preventing isoimmunization. Injury to the placenta, such as occurs during manual removal of the placenta and during Cesarean section, enhances fetal blood trans- fer. Queenan and Nakamoto (1964) found that spontane- ous placental delivery and previous drainage of cord blood minimize the probability of isoimmunization.
Although it is possible that occasional fetal bleeding in early pregnancy may lead to immunization of primigravi- dae, the commonest time of sensitization is at delivery (Scott et al., 1977).
Maternal bleeding into a female fetus presumably accounts only for very few immunizations in their future gestations, when an Rh-negative infant is delivered to an Rh-positive mother (Taylor, 1967). Such mother-to-fetus transfer of blood, however, is said to occur as often as in 43% of samples analyzed by Luca et al. (1978). This feature of maternal–fetal blood exchange is further discussed in Chapter 17.
The amount of immunogen needed for isoimmuniza- tion has been debated. Attempts to elucidate this with experimental findings have been made in Rh-negative volunteers. Zipursky and Israels (1967) suggested that repeated injections of as little as 0.1 mL ABO compatible Rh-positive blood will suffice to immunize Rh-negative individuals. That is an amount that is presumably fre- quently attained in normal pregnancies. Mollison (1968) opined that the minimum amount needed for immuniza- tion is 0.25 mL of fetal blood.
Figure 16.7. Normal term placenta (right) and placenta of erythroblastosis (left). Note the marked pallor and disruption of the erythroblastotic placenta.
Figure 16.8. Placentas of twins as in Figure 17.7. The enlarged, edematous placenta of the diamnionic/dichorionic (DiDi) twins, one with erythroblastosis (left), shows the pallor and bulky cotyledons.
These deliberations are particularly important when one considers whether a hydatidiform mole, spontaneous abortion, or ectopic pregnancy can immunize an Rh- negative woman. Price (1968) reported a case of hydatidi- form mole, followed by a normal pregnancy, in which antibodies were detected at about 6 months; the neonate succumbed from EF. The assumption was made that the mole had immunized the primigravida. It seems unlikely to us that a bloodless structure is capable of Rh immuni- zation, unless the original tissue was a partial mole with triploidy and the possibility of fetal blood content. Alter- natively, it is now proven that early hydatidiform moles may possess some fetal red blood cells, to disappear later (Baergen et al., 1996; Fisher et al., 1997; Paradinas et al., 1997); perhaps their detection by such a mother led to antibody formation. It has also been debated why, in patients having an abortion, it sometimes becomes neces- sary to provide RhoGAM to patients. Freda et al. (1970) came to the conclusion that this was indicated only after the second month of pregnancy. Regrettably, their data do not specify whether the abortions they studied were terminations of pregnancy, or whether they were true spontaneous abortions. The vast majority of the latter cases have no circulating fetal blood as they are due to chromosomal errors that led to embryonic death earlier.
They would not be expected to deliver sufficient antigen for sensitization; there is no doubt, however, that embry- onic erythrocytes are capable of immunization. Examples of this are the cases of therapeutic terminations of early pregnancy studied by Matthews et al. (1969), Jorgensen (1969), Murray and Barron (1971), and Eklund (1981). To be sure, the risk of sensitization is small and it depends also on the type of instrumentation used in the termina- tion of pregnancy, such as suction vs. dilatation and curet- tage. And it also depends on fetal age. Ectopic pregnancies present a significantly higher risk for isoimmunization than that which occurs with spontaneous abortion (Grimes et al., 1981), presumably because of their less frequent cytogenetic abnormality and fewer embryonic deaths. Whether chorionic villus sampling (CVS) pres- ents a risk, is yet to be determined. When Warren et al.
(1985) studied a-fetoprotein (AFP) levels and Kleihauer- Betke stains following CVS, they found AFP levels to rise. They felt that the Kleihauer technique was not suf- ficiently sensitive to detect possible fetal bleeding. But to our knowledge, the risk incurred for isoimmunization from CVS has not been sufficiently investigated. It is generally thought that Rh-positive fetal red blood cells represent the only immunogen to Rh-negative women;
trophoblastic cells were once thought to contain Rh antigen and also produce sensitization, but the later studies detailed above show this not to be the case.
Besides, then every Rh-positive gestation should lead to isoimmunization because of the massive transportation of syncytium to the maternal lung and its subsequent
destruction. Direct immunofluorescent studies with fluo- rescent anti-Rh D-antibodies have shown that fluores- cence may localize to the syncytium (Jarkowski et al., 1964). Goto et al. (1980) extended these studies. They impressively demonstrated, with appropriate controls, that the amount of trophoblastic Rh-antigen decreases with advancing gestation, in contrast to the increasing prevalence on fetal red blood cells. They also showed that it localizes on trophoblastic surfaces, and that it is present in hydatidiform mole. Whether it can be the cause of sensitization remains elusive for reasons alluded to. The newest observations negate such a possibility. The studies by Benachi et al. (1998) have now revealed decisively that the RhD antigen is not expressed by syncytiotrophoblast.
There is no answer to the obvious question as to why it is that not all Rh-negative women with Rh-positive con- ceptuses become immunized. Although the trophoblastic embolization to the maternal lung in all pregnancies was formerly thought to have relevance in this respect, this is no longer held to be so. With the definitive exclusion of the Rh antigen from syncytium, this speculation fails.
Complete absence of AB antigens from trophoblast was also demonstrated by the early studies of Szulman (1972), who did, however, readily identify the antigen in fetal epithelium and in placental capillaries, including in a chorangioma.
NONIMMUNE HYDROPS
In the majority of cases of hydrops fetalis, the etiology is different from that EF, discussed above. Santolaya et al. (1992) found that of the 76 fetuses with hydrops (among 12,572 ultrasound examinations), only 10 were due to immunologic causes and 66 had nonimmune hydrops fetalis. They were unable to assign a cause in 17 cases. Some of the other hydropic fetuses resulted from fetal anemia and heart failure, tri- somies, and other abnormalities. But many other hydropic fetuses are
“idiopathic,” a euphemism for our lack of knowledge of their precise etiology. It must also be cautioned that ascites alone is insufficient for the diagnosis of hydrops, in which case there is generalized edema, and fluid exists in all cavities. This fluid accumulation in the pleural spaces often leads to pulmonary hypoplasia, a condition that is not the cause of the hydrops, however (Green et al., 1990). The placental pathology is similar to that of EF, but substantial differences are also identified in individual cases. Novak et al. (1991) described cases of what they considered to be “hemorrhagic endovasculitis” of the placen- tal vessels with fetal hydrops, although they did not claim causality. This entity is more fully discussed elsewhere (Chapter 12). They depicted obliterated main stem vessels amidst rather nonhydropic villi; usually this is regarded as a postmortem phenomenon. Eight of their 14 cases were stillborn, and most were complicated by hydramnios. In some unexplained cases of fetal hydrops, pathologists may be able to exclude specific causes. Often, they are confronted with a stillborn, frequently a macerated, hydropic fetus, and are asked to provide an idea as to the mechanism that led to the fetal hydrops. In the following pages we review many of the currently known entities of nonimmunologic hydrops, and then discuss idiopathic hydrops fetalis. Larger series dealing with causes of hydrops fetalis are the following reports: Macafee et al.
(1970), Moerman et al. (1982), Hutchison et al. (1982), Nakamura et al. (1987), Machin (1989), Villaespesa et al. (1990), and Lallemand et al. (1999). Watson and Campbell (1986) provided a detailed man-
Placental Pathology in Erythroblastosis 527 agement protocol for such pregnancies. A large review of 600 cases
is provided by Jauniaux et al. (1990), who ascertained that more than 35% of cases could be ascribed to a genetically transmitted disease, similar to that of Lallemand et al. (1999) who thought that 38% of their 94 cases had a chromosomal origin. Chromosomal disorders also ranked first in Jauniaux’s series, with 15.7%, a-thalassemia was second (10.3%), and a wide variety of anomalies followed. They suggested that chromosomal analysis was needed in such cases. Mallmann and colleagues (1991) suggested that perhaps 49 of their 324 cases of nonimmune hydrops represent an expression of immunologic rejection.
Quite uncommonly prenatal trauma (e.g., a motor vehicle accident) has been held responsible for fetal hydrops, and even transitory events have been reported (see Chapter 17).
a-Thalassemia
Normal adult hemoglobin molecules contain two unlike pairs of poly- peptide (globin) chains, the a-chains and the b-chains. In embryonic and fetal life, special forms of hemoglobin are prevalent at different and carefully scheduled times. Abnormal construction of the globin chains that make up fetal hemoglobin results in altered hemoglobins that may be deficient in oxygen-carrying capacity. This, in turn, can lead to abnormal red blood cell shapes, such as occurs in sickle cell disease. In the thalassemias (a- and b-thalassemias), anemic disorders result from a decreased production of normal hemoglobin. These dis- orders are classified according to the chain, which is depressed. Exam- ples include a-, b-, d-, and g-thalassemia (Nathan, 1973).
a-Thalassemia is an inherited abnormality of hemoglobin structure that often causes hydrops fetalis and that was lethal until the event of intrauterine blood replacement. Carr et al. (1995) have now shown in an afflicted Filipina that repeated transfusions before birth can yield a surviving, transfusion-dependent child. a-Thalassemia was also the first type of nonimmunologic hydrops for which an innovative explanation was identified. This complication of pregnancy has occupied much greater attention in this country in recent years because of the immigra- tion of Indochinese with this genetic background. It is also a model for which prenatal marrow transplantation and gene therapy are being considered. Thus, diagnosis is important, as the homozygous condition is lethal and recurrence rate is at least 1 in 4. Detailed screening methods (cresyl blue staining, erythrocyte indices, and iron study) have been described for the couples at risk for this disease (Skogerboe et al., 1992). The pathology seen in the newborn is essentially identical to that of Rh disease. Lie-Injo and her colleagues (1959, 1962, 1968) reported the association of hydrops fetalis and Bart’s (Bartholomew) hemoglobin, in Indonesian families. Since then, this disease has been recognized in Filipinos (Pearson et al., 1965; Nakayama et al., 1986), Thais (Pootrakul et al., 1967; Thumasathit et al., 1968), Chinese (Kan et al., 1967), Germans (Rönisch & Kleihauer, 1967), and Canadian Orientals (with hemoglobin-H disease: Ing et al., 1968; Gray et al., 1972). It probably occurs in other races. The a-thal1 gene has been identified in Kurdish Jews (Horowitz et al., 1966) and in Ashkenazi Jews, but it has there not been associated with hydrops (Goldschmidt et al., 1968). The same is true of American blacks. The frequency of this deletion of a-chain genes is greatest in Indonesians and Chinese (Zeng & Huang, 1985). Hydrops is caused by the homozygous pres- ence of the gene for Bart’s hemoglobin. The four a-chains are herein replaced by four t-chains. The g-chains are often heterogeneous (Vedvick et al., 1979), and different chain composition causes different severities of the disease. In hemoglobin-Bart’s disease, the a- thalassemia, the defective hemoglobin is unable to release its oxygen effectively, which causes tissue hypoxia, fetal cardiac failure, and hydrops (Orkin & Nathan, 1976). It is essentially lethal at birth or very shortly thereafter. The fetal red blood cells in this disorder are fre- quently misshapen; for example, they may be sickled. Cardiac hyper- trophy is often striking, as is the extensive and widespread extramedullary hematopoiesis. The substitution of various types of
hemoglobin chains during development, and the location of their pro- duction in the fetus are complex and have been lucidly portrayed by Nalbandian et al. (1971). Orkin and Michelson (1980) showed, by DNA sequence analysis, that the 5¢-portion of the a-globin structural gene was deleted in a case of a-thalassemia.
The switching of hemoglobins in embryonic development is regulated in a complex manner; it has been studied by Peschle et al. (1985), and by Wood and his colleagues (1985). Different states of DNA- methylation have been identified, but the mechanism that initiates this switch remains unknown. Many other types of neonatal hemoglobin- opathies are known, as for instance hemoglobin-H disease, in which four b-chains constitute the molecule. This particular hemoglobinopathy is prevalent in Orientals and has a wide spectrum of severity, including occasional hydrops. It causes neonatal anemia, and hydrops was described later (Milner et al., 1971; Chen et al., 2000). A comprehen- sive analysis of the various genetic deletions and substitutions of the a- globin gene in hemoglobin-H disease is found in Chen et al. (2000), who studied Chinese patients from different regions in Asia. Hydrops fetalis is uncommon of unheard of in sickle cell anemia and sickle cell b-thalassemia. Both are associated with poor reproductive outcome, however, but generally do not feature hydrops as a complication (Laros
& Kalstone, 1971). A detailed review of many of these considerations was provided by Jonxis (1965). He described details on the switching from embryonic to fetal, and from fetal to adult hemoglobins, and also listed the then known abnormal hemoglobins.
Louderback and Shanbrom (1967) indicated that hemoglobin elec- trophoresis is perhaps the simplest and most widely available tool for the differential diagnosis of the various types of cord blood hemoglobin.
Sexauer et al. (1975) described a simple and rapid electrophoretic method for the analysis of cord bloods. They found that 11% of their 7500 cord blood samples from black newborns contained an abnormal hemoglobin. The methods for genetic diagnosis have now been con- siderably simplified (Lebo et al., 1990), and they have been successfully applied to prenatal diagnosis as well. Kan et al. (1976) accomplished this by molecular hybridization. Rubin and Kan (1985) presented a rapid and decisive method, based on slot-blot analysis. Williamson et al. (1981) and Chang and Kan (1981) showed that, with CVS biopsy, it is easily possible to make the accurate diagnosis of sickle cell disease in the fetus, and of many cases of thalassemia by direct globin gene analysis. It is important to state that appropriate samples of blood must be saved for such studies at autopsy when the etiology of hydrops is uncertain. The aforementioned methods also much facilitate the diag- nosis of heterozygotes that was previously so difficult to accomplish (Terheggen & Kleihauer, 1968). Unusual causes of hemolytic disease of the newborn, such as the g-b-thalassemia reported by Kan et al.
(1972), are also thus delineated.
The placenta in thalassemia does not differ very much
from that of children with classical erythroblastosis, and
histology alone cannot make the correct differential
diagnosis. The placenta, however, is usually even more
enlarged than in erythroblastosis; it is pale, friable, and
edematous. The cytotrophoblast is prominent and, in the
much enlarged fetal circulation, large numbers of red-cell
precursors are found (Figs. 16.9 and 16.10). Hemosiderin
is occasionally seen within chorionic macrophages, but it
may also be bilirubin pigment from bilirubinuria and
liver damage. Hemosiderosis of the placenta has also
been a feature of b-thalassemia (Birkenfeld et al., 1989),
although Knisely (1990a) cautions that iron occurs in
many placentas. On the whole, Birkenfeld and colleagues
were probably correct in their interpretation, because
total iron content was compared with the normal and was elevated. The placental enlargement in thalassemia has often been massive. Thus, the placenta shown in Figure 16.9 weighed 1900 g. Lie-Injo et al. (1968) described weights up to 3500 g (!), most of which is water. They observed a set of fraternal twins, wherein one of the pla- centas was normal and the other was abnormal. This con- clusively established that the pathologic changes in the placenta have a fetal cause. Pregnancy-induced hyperten- sion (preeclampsia) is a frequent corollary of this con- dition, presumably because of the massive placental enlargement (Suh, 1994). This author also showed hema- topoiesis in the fetal dermis and, by electrophoresis, that 91.2% of the fetal hemoglobin was abnormal.
It is of related interest to be aware of the complex relationships that exist between placental weight (and
edema) to fetal and to maternal anemia. These aspects have been studied by Beischer and his colleagues (1968).
These investigators found that the placental weight of mothers with various types of anemia was in an approxi- mately normal range whereas the placental weight in cases of EF was much more increased, even when com- pared with the enhanced placental weight found usually in the pregnancies of diabetic mothers. Other aspects of clinical management are important. Thus, Guy and col- leagues (1985) studied five pregnant Oriental women sonographically and found that sonographic surveillance for hydrops was an invaluable tool in clinical manage- ment (see also Saltzman et al., 1989 for criteria). These investigators emphasized that the pregnancies were fre- quently complicated by preeclampsia, and by retained placentas that necessitated manual removal. Miller et al.
Figure 16.9. Placenta in a-thalassemia with fetal hydrops.
This placenta weighed 1900 g and had macroscopic fea- tures such as the organ in Figure 16.8. Note the large number of marrow-like elements in the fetal capillaries.
H&E ¥640.
Figure 16.10. Villi of macerated, hydropic fetus showing edema and numerous hyperchromatic cells intravascularly.
Neuroblastoma was suspected but could not be proved.
H&E ¥350.
(1987) reported theca-lutein cysts in a Vietnamese mother who had hydramnios and an hydropic 1290-g infant who died immediately after birth. The placenta weighed 1600 g.
The ovarian cysts are attributed to elevated hCG levels from the enlarged placenta. The mother’s b-chain hCG levels were 1,120,000 mIU/mL. The gonadotropin levels fell rapidly to 83.8 mIU/ml within 15 days, and her ovarian masses disappeared. This is not unlike the cases of ovarian cysts that may accompany EF. Mouse models of this dis- order have been described. Their potential usefulness for the elucidation of yet unknown aspects of this disease was discussed by Whitney and Popp (1984). With the increas- ing population of Vietnamese and other Orientals in this country, a-thalassemia is seen more frequently and must be routinely considered in the differential diagnosis of hydrops (Suh, 1994). As more prenatal sonography is now being practiced, new methods are being sought in early diagnosis of these diseases. Thus, Lam et al. (1999) found that the cardiothoracic ratio may be significantly elevated in a-thalassemia as early as at 12 to 13 weeks’
gestation.
New hematologic disorders have come onto the horizon as the genome is being explored in greater detail. Thus, Gallagher et al. (1995) described the occurrence of fatal anemia in two children (due to red cell membrane insta- bility) with hydrops. The instability was the result of a homozygous mutation of the b-spectrin gene, producing the spectrin “Providence.” The Diamond-Blackfan anemia was found to be the cause of hydrops in two children described by Rogers et al. (1997). One child survived after prenatal transfusions and needs lifelong transfusion.
The other, born with a hematocrit of 10% and a hydropic placenta, died neonatally. Interestingly, the islets of Lang- erhans were much enlarged, a condition here assumed to be secondary to anemia. Methemoglobinemia was the cause of hydrops in a case described by Özmen et al.
(1995). The pregnancy was terminated and the placenta was not described.
Fetal Hemorrhage
Hydrops fetalis has repeatedly been the result of massive and usually chronic fetomaternal hemorrhage, and it is for that reason that it has been our practice to examine maternal blood for fetal cells (Kleihauer-Betke tech- nique, see Chapter 17) in all cases of unexplained still- births. As in EF, when the hemoglobin levels fall below a certain point (about 7 g/dL, or a hematocrit of approxi- mately 15% or less), cardiac failure may cause hydrops.
When the fetal exsanguination is rapid, it does not produce hydrops so quickly and may result more likely in fetal death. It requires ensuing heart failure and tran- sudation for hydrops to occur. This complex aspect of adjustments was discussed in the case presented by
Herman et al. (1987), with a fetal hematocrit of 15% and hemoglobin of 3 g/dL at term. In that case, the mother had a 2.8% Kleihauer test result (which equals approxi- mately 150 mL fetal blood) and no placental abnor- malities were found. Bowman et al. (1984) considered transplacental hemorrhage to be an exceptional cause of fetal hydrops. They reviewed the few cases from the literature and described a neonate in whom large and chronic, bidirectional blood exchange must have occurred.
The placenta showed major fetal vessels to have rup- tured that were believed to explain this phenomenon, and there were also many placental infarcts. The placenta was not markedly enlarged (560 g). No untoward acci- dents had occurred until 31 weeks, when the mother experienced a rapidly increasing abdominal girth. The authors suggested that the hydrops resulted from fetal hypervolemic heart failure. Cardwell (1988) described an hydropic 2750-g liveborn infant who had been treated by prenatal transfusion at 21 weeks’ gestation. The Klei- hauer test had been 0.4%, which corresponded to a 50%
loss of fetal blood. The finding of NRBCs in the fetal circulation is herein also an important pathologic finding (Fox, 1967). Villaespesa and colleagues (1990), who investigated 59 cases of nonimmune hydrops, felt that right-sided cardiovascular failure should be investigated, as 50% of their cases were due to this mechanism. This is borne out by direct measurements of venous pressures in hydropic fetuses (Johnson et al., 1992).
We have now seen many hydropic neonates with veri- fied fetomaternal hemorrhage. One had the hemorrhage after an amniocentesis, which was done to ascertain fetal maturity (0.3% Kleihauer; hematocrit 19% 3 days later).
Another fetus exsanguinated for no known reason (shown in Chapter 17). A third newborn had an 18% hematocrit at birth, and could not be revived. Many NRBCs were found in villous vessels. All three placentas were extremely pale and edematous, but were not so overtly hydropic as in thalassemia. Other cases have since surfaced and I believe that this is not so uncommon a cause of hydrops (certain fetal demise) as had once been believed. It is important, however, to note that ABO incompatibility between mother and fetus may rapidly remove the fetal red blood cells on which (by Kleihauer test) we rely to make the diagnosis of transplacental hemorrhage.
This is an important consideration that will be further elaborated upon in Chapter 17. Zwi and Becroft (1986) reported a patient with ulcerative colitis who was on prednisone and sulfasalazine therapy; the fetus devel- oped hydrops fetalis at 24 weeks’ gestation, after 4 weeks of vaginal bleeding. No fetal red cells were identified in this blood, but a marginal separation of a 460-g edema- tous placenta had occurred. The macerated fetus weighed 1070 g. It had a dilated and enlarged heart, and there was complete absence of hematopoiesis in the liver and bone marrow. The latter finding led the authors to suggest
Fetal Hemorrhage 529
that aplastic anemia was the cause of the fetal hydrops and placentomegaly. The cause of the anemia was not determined, but it is noteworthy that the mother’s sulfasalazine therapy had been discontinued in early pregnancy.
Fetal Tumors
Congenital neuroblastoma has repeatedly been shown to cause fetal death. Birner (1961) described such a fetus and found an unusually enlarged placenta (1240 g). The 3925-g fetus was slightly edematous and macerated, but the placenta did not contain neuroblastoma cells.
The villi were enlarged, edematous, and had an increased number of Hofbauer cells. Additionally, Langhans’ cells had persisted to term.
Strauss and Driscoll (1964) were the first authors to draw attention to the involvement of the placenta with neuroblastoma metastases. Their first fetus was edematous and resembled an erythroblastotic infant. The placenta was markedly enlarged and friable, and it also resembled that of EF. Cords of neuroblastoma cells were found in fetal capillaries.
Their second infant was born at term, and it was accompanied by a 1030-g placenta. Typical neuroblastoma cells and erythroblasts crowded the fetal capillaries (Figs. 16.10 and 16.11). The fetal heart was enlarged. The first mother had theca lutein cysts, similar to those mentioned earlier in this chapter. Other cases of fetal hydrops with congenital neuroblastoma and placentomegaly have since been described (Anders et al., 1973; Moss & Kaplan, 1978; Slikke & Balk, 1980; Perkins et al., 1980; Smith et al., 1981; Newton et al., 1985).
A possible immune hypothesis for the development of the hydrops was entertained by Strauss and Driscoll (1964), but most authors have now discounted this possibility. Hydrops and placentomegaly were present in Birner’s case (1961), but there was no placental neoplasm. This finding suggested that it was not the plugging of fetal capillaries with tumor cells that causes the placentomegaly and this could thus not be the etiology of hydrops. The case of Newton et al. (1985) may have relevance to the considerations of pathogenesis. Their case was asso- ciated with maternal hypertension, which was presumed to be caused by the production of catecholamines from the fetal neuroblastoma.
Perhaps, similar changes of blood pressure occur in the fetus and contribute to fetal heart failure. Perkins et al. (1980) found, in a case of congenital neuroblastoma, that the villous tissue, too, was infiltrated by neuroblastoma cells and that these contained cytoplasmic granules, which, electron microscopically, were typical of neuroblastoma cells.
We have seen placental hydrops with a severely hydropic and macer- ated fetus in whose placental vessels there were many malignant small cells. A positive diagnosis of the neoplasm was impossible (Fig.
16.12). No tumor mass existed in the fetus. The most recent review of the 11 cases of placental neuroblastoma with fetal hydrops reported comes from Lynn et al. (1997). They concluded that, after careful review of all factors, the pathogenesis of hydrops remains to be identi- fied. They ruled out secretory products from the neuroblasts as mechanism and provided guidelines for a differential diagnosis, as they showed the tumor cells to be positive for neuron-specific enolase, negative for cytokeratin, desmin, synaptophysin, and bcl-2. Determina- tions of atrial natriuretic factor and aldosterone concentrations showed them to be elevated in hydrops fetalis due to anemia (Ville et al., 1994a,b). Perhaps future studies need to concentrate on such determi- nations for an explanation of the development of hydrops fetalis in general. It should be pointed out also that not all cases of congenital neuroblastoma are associated with hydrops. This was shown, for instance, in the two patients described by Ohyama et al. (1999) whose tumors were diagnosed by placental examination. These authors also referred to additional congenital cases and described additional differential diagnostic tests.
Very similar in its placental manifestation was the hydropic preg- nancy described by Doss et al. (1998) that was the result of a fetal hepatoblastoma. The villous capillaries of this enlarged placenta (1190 g at 33 weeks) were filled with immature cells, metastatic from the hepatic lesion. The tumor cells stained positively for a-fetoprotein.
Oetama et al. (2001) described fetal hydrops due to an epithelioid hemangioendothelioma of the fetal bone marrow space. Uniform mono- cyte-like cells dominated the blood smear, and there was a large number of NRBCs as well. This is a difficult diagnosis to make and it would be even harder in macerated fetuses.
Sacrococcygeal teratomas also produce placentomeg- aly and fetal edema. They are frequently accompanied by hydramnios and elevated hCG levels (Barentsen, 1975).
In the first two such cases described, the placental edema and large number of NRBCs in the villous capillaries were identical to that seen in placental erythroblastosis (Kohga et al., 1980). When we wrote this paper, we sug- gested that high-output cardiac failure produced the hydrops. This was confirmed by the study of Langer et al.
Figure 16.11. Villus of case with congenital neuroblas- toma. The enlarged villus has numerous neuroblastoma cells in fetal vessels, some of which show some rosetting.
H&E ¥400.
(1989). These authors observed such a tumor at 21 weeks’
gestation with hydrops and placental edema. After they attempted to remove the tumor they observed a diminu- tion of hydrops and a reduction in placental thickness.
Other cases of sacrococcygeal teratoma, hydramnios, hydrops and placentomegaly (occasionally associated with preeclampsia) are reviewed in this publication and those of Perlin et al. (1981), Feige et al. (1982), Holzgreve et al. (1987), Kuhlmann et al. (1987), Pringle et al. (1987), Bock et al. (1990), and in an intrapericardial teratoma by Sklansky et al. (1997). These reports present additional cases that may be consulted for completeness. The usual prenatal recognition of this tumor has now also led to successful therapy. Adzick et al. (1997) found in a fetus with such a tumor that the hydrops and placentomegaly markedly increased between 20 and 25 weeks. The tumor was then resected in utero, whereupon the hydrops disap- peared and the 29-week-gestation child was electively delivered by cesarean section and did well.
Fetal placental leukemia is rare. Macroscopically, it resembles erythroblastosis fetalis and causes placento- megaly. Figure 16.12 shows a 1000-g placenta in presumed fetal leukemia that came with a severely macerated fetus that was not autopsied. We have seen only one other similar case, which involved a fetus with trisomy 21.
Various angiomas have repeatedly caused hydrops fetalis and placentomegaly (see Chapter 24). For instance, Imakita et al. (1988) described a patient with severe hydramnios at 31 weeks’ gestation; there were sono- graphic features of hydrops fetalis and a large chorangi- oma. After an amniocentesis, the patient delivered 2 days later but the infant died at 2 days of age. The neonate’s
hemoglobin content was 15 g/dL; there was hypoprotein- emia but no evidence of iso-immunization. The fetal heart was markedly hypertrophied and dilated, and the 840 g placenta had a 5.5 ¥ 4.5 ¥ 3 cm chorangioma. The authors conjectured that the location of the angioma may have been such as to have obstructed the venous return from the placenta. They also reviewed many previously reported cases of the association of chorangioma with hydrops. No doubt, in this case also, high-output cardiac failure of the fetus was responsible for the hydramnios and the placentomegaly. An interesting case of fetal hydrops, resulting from a complex hemangioma of the umbilical cord, was presented by Seifer et al. (1985). This occurred in one of dichorionic female twins who weighed 2100 g at birth but who lost her edema over the course of the first month of life. The birth weight of the co-twin was 1670 g. High-output failure was thought to have been caused by an angioma in the umbilical cord that mea- sured 9 cm in diameter and 18 cm (!) in length. This enlargement was mainly due to edema, however. The placenta was otherwise normal. Hepatic angiomas of the fetus are occasionally so large as to cause fetal heart failure (Gonen et al., 1989; Skopec & Lakatua, 1989) and may be associated with significant neonatal thrombocy- topenia. We have seen such a case in which the left lobe of the liver was replaced by a cavernous angioma. The remainder of liver had extensive centrolobular ischemic necrosis, and the kidneys were acutely infarcted. The neonate had cardiomegaly, a markedly hydropic placenta (1050 g), and an increase in NRBCs (Fig. 16.13). The neonate expired in 2 days. In cases of prenatally recog- nized nonimmune hydrops fetalis, sonographic study may
Figure 16.12. Placenta from macerated stillborn with pre-sumed leukemia. The villous capillaries are packed with leukemic cells, and some stromal infiltration is also seen.
(Courtesy of Dr. E.V. Perrin.) H&E ¥60; ¥160.
Fetal Hemorrhage 531
identify such tumors as a cause of hydrops. In the past, Dr. A. James McAdams had shown us a 7-month-old child with a presumed hepatic “hamartoma” in whom the hydropic placenta had weighed 1320 g. Of course, acardiac twins may present so much of a hemodynamic burden to the normal “donor” that hydrops can occur in that donor twin. It is an indication for prenatal ablation of the acardiac. Such a circumstance was recorded by Harkavy and Scanlon (1978) and is further discussed in Chapter 25.
Maternal disease, other than hydramnios, has occasion- ally occurred with large chorangiomas. Thus, Dorman and Cardwell (1995) observed a patient with a large placental angioma who suffered Ballantyne syndrome, a combina- tion of severe edema, hypertension, and eclamptic fits that resolved promptly after elective delivery. Interest- ingly, the pregnancy was not accompanied by hydramnios.
Three additional patients were described by Selm et al.
(1991), who discussed the possible etiology of this complex but rare syndrome.
Cystic-adenomatoid malformation (CAM) of the lung, while not a true neoplasm, is another well-recognized cause of fetal hydrops and placental edema. Figure 16.15 shows the markedly hydropic placenta of the case pub- lished by Gottschalk and Abramson (1957). In this case, autopsy findings indicated that the mediastinum had shifted and had thus caused a chronic impediment to venous return from the placenta. The fetal heart was one- half the expected size; the placenta was edematous and weighed 1105 g, at 27 weeks’ gestation. The authors cited
Figure 16.13. Edematous villi with capillaries stuffed with red cells precursors (left) in hydropic patient with cavernous hepatic angioma (right). H&E ¥250; ¥60.
additional similar cases. We saw such a case sonographi- cally in one twin, with shift of the mediastinum, and Bromley et al. (1992) reported a similar set of twins. An infant with anasarca, whose placenta was not described, had a successful removal of such a large “tumor” (Aslam et al., 1970). Clark et al. (1987) even operated successfully on a hydropic child with cystic adenomatoid malforma- tion after having placed an intrathoracic shunt prenatally.
Ascites and subcutaneous edema disappeared, and the child delivered normally 17 weeks later. The tumor was removed on the first day of life. These authors and Kohler and Rymer (1973) cited additional cases of hydrops with adenomatoid malformations of the fetal lung. Occasional other tumors may also be associated with hydrops or cause fetal hydrops; some only produce polyhydramnios.
Thus, Gray (1989) reported the latter condition with a mesoblastic nephroma. Fung et al. (1995) also found polyhydramnios associated with a fetal mesoblastic nephroma and believed the calciuria to have been respon- sible for the polyhydramnios. In neither case was the placenta described.
Congenital Anomalies and Hydrops Fetalis
Aside from the adenomatoid malformation of the lung,
numerous other congenital anomalies have been causally
or otherwise related to the development of fetal hydrops.
Benacerraf and Frigoletto (1986) diagnosed the presence of a diaphragmatic hernia and then drained a large right hydrothorax; the fetus survived and was born without further complications. The placenta was not described.
The Klippel-Trenaunay syndrome (angio-osteohypertro- phy) has occurred with hydrops fetalis (Mor et al., 1988).
The placenta weighed 760 g and was bulky and friable.
The newborn had giant port-wine nevi and high-output cardiac failure. Seward and Zusman (1978) reported the case of a hydropic newborn that had fetal anemia, perhaps due to a small bowel volvulus. Brinson and Goldsmith (1988) reported a child with intrauterine intussusception and intestinal perforation; hypoproteinemia was therein presumed to have caused the hydrops. Pulmonary seques- tration has often caused nonimmune hydrops (Weiner et al., 1986), presumably also because of an obstructed venous return to the heart. The placenta in this case was normal. Several cases of hydrops in Noonan’s syndrome have been described (Bawle & Black, 1986;
Oudesluys-Murphy, 1987); the associated placentas were not mentioned. Koffler et al. (1978) described two cases of chylothorax that were associated with hydramnios, in the absence of hydrops; the placenta was not mentioned.
Both infants survived. A similar case comes from Sacks et al. (1983), who stated that the placenta was not enlarged.
Chylothorax and lymphangiectasis are occasionally the causes of hydrops. Abnormal development of lymphatics may be responsible for generalized edema (Windebank et al., 1987). These authors identified abnormal connec- tions of lymphatics and vessels in an hydropic infant.
They were also associated with cystic hygroma, a feature that may be at the basis of the edema in 45,X fetuses (Turner syndrome). Alternatively, coarctation of the aorta may be causative (Lacro et al., 1988). But the placenta in Turner’s syndrome is not truly hydropic. If anything, it is smaller in size, and occasionally has the features of a Breus’ mole (subchorionic tuberous hematoma). We have observed a set of monozygotic twins with abnormal chro- mosomes; one was 46,XX and normal, the other was 45,X and had massive edema, ascites, and cervical hygroma. A similar set of discordant monozygotic (MZ) twins (46,XY and 45,X) with hydrops in the latter twin was reported by Gonsoulin et al. (1990). Many reports on chromo- somal trisomies suggest that these anomalies are an occa- sional cause of hydrops. Landrum et al. (1986) found that 17 cases of hydrops with trisomy 21, six with trisomy 18, and two with trisomy 13 had been reported. They added three cases with trisomy 21, and one with trisomy 13 of their own. Hendricks et al. (1993) also found two cases of hydrops with trisomy 21 and an associated but transitory myeloproliferative disorder, and anemia. It is of interest to note here that, in a case of chromosome 18p- syn- drome, the fetal hydrops was probably due to complete heart block, resulting from calcifications in the atrioven- tricular node (Bridge et al., 1989). Schwanitz and col-
leagues (1988) have reported hydrops fetalis in a child with duplications of the long arms of chromosomes 15 and 17, offspring of a parent with balanced 15/17 translo- cation. They suggested that a chromosomal analysis should be undertaken in every case of nonimmune hydrops in which the cause has remained obscure. The cause of hydrops in these infants is unknown (see also Watson & Campbell, 1986), and the placenta is rarely discussed. Greenberg et al. (1983) described hygromas and hydrops in a fetus with trisomy 13 and cautioned that hygromas are not necessarily due to monosomy X; the macerated fetus had many other anomalies, but the pla- centa was not described. Gropp (1984) found similar con- ditions of edema in the experimentally induced mouse trisomy. He evaluated the various reported suggestions that seek to explain the fetal hydrops. The Neu-Laxova syndrome is another cause of hydrops; it is accompanied by multiple anomalies, hydramnios, and occasional pla- cental edema (Broderick et al., 1988). It has also been reported that congenital myotonic dystrophy may lead to hydrops and pleural effusions but the status of the pla- centa was not described (Curry et al., 1988). Tuberous sclerosis has also been implicated in the genesis of hydrops fetalis. Östör and Fortune (1978) described such a case, but did not mention the placenta. The hydrops was presumably secondary to the cardiac rhabdomyoma present.
Congenital Heart Disease
Numerous cases of congenital heart disease have been described as being accompanied by hydrops fetalis. Best known among these perhaps are Ebstein’s anomaly of the tricuspid valve (Moller et al., 1966), endocardial fibro- elastosis (Ben Ami et al., 1986), premature closure of the foramen ovale (Rodin & Nichols, 1975; Olson et al., 1987), and some forms of hypoplastic left heart (Leake et al., 1973). Many other types of anomalies have been listed, too numerous for this discussion. Some are listed by Kleinman et al. (1982), who did not have any cases of idiopathic hydrops. They reported 10 cases of cardiovas- cular anomalies, and three with supraventricular tachy- cardia. These authors emphasized the importance of fetal echocardiography. McFadden and Taylor (1989), in their review of a large series of congenital heart disease and nonimmune hydrops, expressed the view that the coinci- dence of the two conditions was not causally related.
They were especially emphatic in pointing out that pre- mature closure of the foramen ovale was not a cause of hydrops fetalis. Graves and Baskett (1984) reviewed 26 cases of nonimmune hydrops fetalis. They found 11 cases with anomalies and five with primary heart malformation.
There were also four cases of the twin transfusion syn- drome. In a set of twins whose placenta did not show
Congenital Heart Disease 533
