Paper - Pathological changes in the placenta associated with erythroblastosis of the fetus (1938)

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Hellman LM. and Hertig AT. Pathological changes in the placenta associated with erythroblastosis of the fetus. (1938) Am J Pathol. 14(1):111-120. PMID 19970373

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This historic 1938 paper by Hellman and Hertig describes placenta pathology associated with erythroblastosis of the fetus.

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Pathological Changes in the Placenta associated with Erythroblastosis of the Fetus

Louis M. Hellman, MD., and Arthur T. Hertig, M.D.

From the Department of Pathology and the Department of Obstetrics, Harvard University Medical School and the Boston Lying-in Hospital, Boston, Mass.

  • Received for publication July 30, 1937.
  • Description of the placenta contributed by Hertig.

One of the earliest writers to recognize the importance of congenital edema of the fetus was Ballantyne. He collected 70 cases, including those that had appeared in the literature and those that had come to his own personal notice. While the edema noted in many of these infants seemed to be due to obvious congenital defects, there were a few cases that showed no obvious etiological factor. It is this latter group that we have classified as part of the general syndrome of erythroblastosis, and it is in this group also that first mention is made of the gross placental changes in fetal dropsy.

Schridde,’ first recognizing the underlying pathological changes associated with congenital hydrops, merely mentioned the placentas as showing edema both grossly and microscopically. In the same year Sitzenfrey * noted both edema and hyperplasia of the stroma of the villi. Nyhoff* stated that the villi were necrotic. Esch,® Eichelbaum,® Weiner,’ and Kovacs * also noted edematous changes in the villi. Goormaghtigh ® felt that there was erythroblastic proliferation and infiltration of the stroma.

Diamond, Blackfan, and Baty ?° in an extremely comprehensive article on erythroblastosis have given a complete survey of the literature. In many of their references the authors have taken passing notice of the placental changes. This is especially true where the striking gross changes associated with congenital hydrops occur. In the same paper there appears a short microscopic survey of the pathological changes in the placenta.** For the first time mention is made of the apparent immaturity of the placenta. This feature has been similarly emphasized by Clifford and Hertig.”

At no time, however, has a systematic examination of the placentas associated with both congenital hydrops and icterus gravis been recorded. It is the object of this investigation to record the histopathological changes in the placentas of infants suffering from erythroblastosis. For this purpose erythroblastosis has been divided into two subgroups — congenital hydrops and icterus gravis. The diagnosis of erythroblastosis has been made on finding, either clinically or at postmortem examination, an enlarged liver and spleen associated with an abnormal number of circulating nucleated red cells and extramedullary erythropoiesis. The term congenital hydrops has been used to designate the additional finding of anasarca, with or without icterus. The infants showing the additional finding of icterus without anasarca were classified under the term icterus gravis (Hellman and Hertig 2”). The majority of the cases herein presented occurred in the Boston Lying-in Hospital between the years 1931 and 1937. A few cases, however, were submitted to the pathological laboratory of this hospital for confirmation of diagnosis. These have been included with the permission of the attending physicians. The mothers of all the infants had negative blood tests for syphilis.* In addition, the liver, spleen and placenta of all infants in the hydrops group were stained for spirochetes by the Levaditi method. In no instance were any spirochetes found. For the sake of brevity only 1 case in each of the two groups will be presented in detail. The remainder will be presented in tabular form.

Presentation Of Cases

Type 1. Congenital Hydrops

Case 1. Mrs. H. B., No. 71756. The mother was a 29 year old, white, American-born para 5. She had had 2 normal children, 2 miscarriages and 1 stillbirth. Her prenatal course during this pregnancy was normal until 2 weeks prior to admission to the hospital when she began to have headaches. She developed a rapidly progressive type of toxemia and was admitted to the hospital as an emergency case. On admission she had edema of the hands, face and extremities, a blood pressure of 150/go, and a large trace of albumin in the urine. The laboratory test for syphilis was negative. In spite of all therapy she became progressively worse. On March 24, 1937, when she was 8 weeks from term, a Braxton Hicks version was performed and a foot brought down. She was subsequently delivered of a 2880 gm. stillborn female infant with advanced generalized edema. The clinical diagnosis of erythroblastosis of the hydrops variety was confirmed at postmortem examination.

Description of Placenta

The placenta weighed 1260 gm. The membranes were complete but badly lacerated. The fetal surface was smooth, shiny, gray in color and translucent. The cord showed no gross pathological change other than edema. The maternal surface was intact, a pale yellow gray, deeply fissured and extremely friable (Fig. 1). There was no calcification of the decidua. The placenta cut with increased resistance and the cut surface was a pale yellow gray and firm in consistence. The villi could be easily teased out.

The Hinton test for syphilis was used throughout.

On microscopic section the villi were larger than normal. The syncytial cells were large, and the nuclei were regularly spaced, large and vesicular. There were frequent paranuclear clear spaces which had a tendency to depress the adjacent nuclei. These vacuoles contained neither stainable fat nor glycogen. There were few so-called nuclear knots. There was a partial persistence of Langhans’ layer. The villi presented stroma of both the hyperplastic and the edematous types, but the former was by far the more common. The hyperplastic type of stroma was made up of small cells with well stained acidophilic cytoplasm and small dark nuclei. The edematous type of stroma had fewer cells and these were widely separated by clear spaces. These cells were large, had a basophilic or pale acidophilic cytoplasm, were multipolar and gave off long fibrils. The nuclei were large and vesicular with peripherally arranged chromatin. In the interstices were many large mononuclear cells with a granular acidophilic cytoplasm (Hofbauer cells) which was often vacuolated. These vacuoles contained fat. The vessels were diminished in number and had a tendency to be arranged peripherally. The endothelium of the vessels was made up of large cells whose nuclei projected into the lumens of the vessels. The capillaries and larger vessels were all filled with nucleated red cells. In the villi with hyperplastic stroma were many foci of intracapillary erythropoiesis which showed red cells in all stages of development (Fig. 4). There were a few areas of subsyncytial fibrinoid deposition. The decidual and chorionic plates showed no pathological changes.

Type 2. Icterus Gravis

Case 2. Mrs. S. L., No. R.H. 2673. The mother was a 38 year old, white, American-born para 2. Her first child was normal. The prenatal course during this pregnancy was entirely normal. The laboratory test for syphilis, although not done during the prenatal period, was negative on a follow up visit. She was delivered normally at term on Dec. 10, 1932, of a 3360 gm. male infant. The child was covered with a golden yellow vernix and was quite cyanotic at birth. He never breathed well. Shortly after birth he developed petechiae in the scalp. The liver and spleen were enlarged to palpation. Examination of the blood showed 4,100,000 red cells and 14,000 nucleated cells, 64 per cent of which were red cells. The hemoglobin was 105 per cent. The clotting time was 30 minutes, the bleeding time normal. In spite of a transfusion of 30 cc. of mother’s blood the child continued to fail. The nucleated red cell count rose to 80 per cent of the nucleated cells. Jaundice appeared on the 2nd day and the child died shortly thereafter. Permission for a postmortem examination was not obtained.

Congenital Hydrops

Table I
Case No. Age Parity

Case submitted by Dr. A. E. Steele, Lawrence Memorial Hospital, Medford, Mass. +Case submitted by Dr. R. Durkee, Hartford Hospital, Hartford, Conn. [116]


Icterus Gravis

Case No.



oO! placenta

Weight of


Size of villi

PerSyncytial] sistence | Epithelial] Hyper- | Edemlegener- of vacuoli- | plastic atous ation Langhans’ zation stroma | stroma ayer

Diminu tion of vessels

Immature endothelium

Nucleated red cells




E.N. 5435

am. 810

om. 3090


S.L. R.H.2637




CS. 11649




D.B. 16449



G.F. 16827




++ ++ + +

AF. 8844




++ + +

EN. 5435




Description of Placenta

The placenta weighed 570 gm. The membranes were complete but were stained a slight yellow. The chorionic plate was thin, smooth and glistening. ‘The maternal surface was intact, showed normal fissuring, and there was no calcification. There were several small areas of ischemic necrosis of the villi. The placenta cut with the usual resistance and the cut surface was pale reddish yellow. It was not unusually friable. The cord showed no pathological changes.

On microscopic section the villi were slightly increased in size. The syncytial cells were slightly larger than usual and the nuclei were more evenly spaced. The nuclei were large and vesicular and there were many paranuclear clear spaces that had a tendency to depress the adjacent nuclei. The so-called nuclear knots were somewhat reduced in prominence. There was a partial retention of Langhans’ layer. The epithelial layers showed little degenerative change. The cellularity of the stroma was increased but was mostly of the edematous variety and the hyperplastic type was not as evident as in the placenta of Type 1. The same large cells with multipolar processes were present. In the interstices were many Hofbauer cells, most of which showed cytoplasmic vacuoles. The vessels were somewhat reduced in number but their endothelium showed no pathological changes. There were no areas of erythropoiesis but all the vessels contained nucleated red cells. The chorionic and decidual cells showed no pathological changes.


Table I records the gross and microscopic pathological changes in 16 placentas from infants suffering from erythroblastosis of the hydropic variety. The infant mortality in this group was 100 percent and the diagnosis in each instance was confirmed by postmortem examination. In considering these pathological changes only the outstanding deviations from normal have been recorded. In an effort to give some estimate of the magnitude of this deviation, the symbols +, +-++, and +-+--+ have been used. A blank space represents no deviation from the normal. These values were based on the opinion of one individual and in spite of the necessarily attendant error showed a remarkable consistency.

The pathological changes tabulated in Table I are also shown in the microphotographs (Figs. 2-5). The placentas were nearly double the normal weight and the fetal placental ratio was reduced from the normal of 6:1 to 3:1. Grossly the placentas presented a friable gray maternal surface which was quite distinctive. Microscopically the villi were increased in size, epithelial degeneration was reduced to a minimum, and there was an abnormal persistence of Langhans’ layer, which should have entirely disappeared by the 5th month. Vacuolization of the epithelium was present in each instance. Definite changes in the stroma were also noted. There was a diminution in the number of vessels and the endothelial cells were large and immature. Nucleated red cells were always present and foci of erythropoiesis were noted in all but 3 of the placentas.

The 7 placentas recorded in Table II were from infants suffering from erythroblastosis of the icterus gravis variety. The presence of the disease in these infants was proved either at autopsy or by the clinical findings of an enlarged liver and spleen, jaundice, and a greatly increased number of circulating nucleated red cells. The placentas in this group were normal in weight but, as can be seen in Table II, they presented microscopic pathological changes varying only in degree from those seen in the preceding group.

It is felt that the changes here described constitute a pathological syndrome pathognomonic of erythroblastosis. The cause of these pathological changes is obscure. However, it is worth noting that the immature placenta, especially during the period of its greatest growth, shows epithelial, stromal and vascular changes reminiscent of those described above. However, erythropoiesis and nucleated red cells are never seen in the abundance in which they occur in erythroblastosis. It is of interest, too, that anaplastic proliferating epithelium from hydatidiform moles and cases of chorionepithelioma shows vacuolization similar to that seen in the immature placenta and the erythroblastic placenta. The presence of the Hofbauer cells in the immature placenta and that of erythroblastosis is of undetermined significance.

The resemblance of these pathological changes to those described as occurring in the syphilitic placenta is striking. Grossly the placentas are similar except for the peculiar fatty surface attributed to the syphilitic placentas. Microscopically the villi in both types are enlarged. Here, however, the resemblance ends, for the pathological changes described as being due to erythroblastosis do not resemble the fibrosis, obliteration and round cell infiltration of villous vessels attributed to syphilis. Although syphilis probably does produce certain changes in the placenta, it is the consensus of current opinion that too often the presence of a positive maternal Wassermann has led to a diagnosis of syphilis of the placenta when the changes present were due primarily to immaturity. A more careful consideration of the autopsy and placental material in these cases would probably disclose a number of cases of erythroblastosis. It is certain that the postmortem examination of every stillborn infant should include both gross and microscopic examination of the placenta.

Summary and Conclusions

  1. Sixteen placentas from infants suffering from erythroblastosis of the hydropic variety and 7 from infants suffering from erythroblastosis of the icterus gravis variety are presented.
  2. Pathological changes in the epithelium, stroma and vascular tree are described which constitute a pathological syndrome pathognomonic of erythroblastosis of the hydropic variety.
  3. Similar, but less advanced pathological changes are present in placentas from infants suffering from erythroblastosis of the icterus gravis variety.
  4. These pathological changes resemble to some extent those seen in immature placentas and in the epithelium from hydatidiform moles and cases of chorionepithelioma.
  5. The resemblance of these pathological changes to those attributed to syphilis is discussed.
  6. In our experience no other disease of the fetus produces a similar picture in the placenta.


1. Ballantyne, J. W. The Diseases and Deformities of the Foetus. Oliver & Boyd, Edinburgh, 1892-1895.

2. Schridde, H. Die angeborene allgemeine Wassersucht. Munchen. med. Wehnschr., 1910, 57, 397-398.

3. Sitzenfrey, Anton. Gdem der Placenta und kongenitale akute Nephritis mit hochgradigem universellen Gdem bei Zwillingen, die von einer an akuter Nephritis leidenden Mutter stammen. Zentralbl. f. Gynak., IQIO, 34, 1381-1386.

4. Nyhoff, G.C. Zur Pathologie des Hydrops universalis foetus et placentae. Zentralbl. f. Gynak, 1911, 35, 808-814.

5. Esch, P. Das kongenitale Lungenadenom und seine Beziehung zum Hydrops fetus universalis und Hydramnion acutum. Arch. f. Gynak., 1928, 133, 32-39.

6. Eichelbaum, Hans Reinhard. Uber die Erythroblastose (Hydrops congenitus) der Neugeborenen und ihre Beziehung zum _ Icterus neonatorum. Arch. f. Gynak., 1923, 119, 149-162.

7. Weiner, G. Oedéme généralisé du foetus avec ascite congénitale; hydropéricarde; lymphangiome kystique du cou et placenta pseudokystique. Bull. Soc. @obst. et de gynéc., 1928, 17, 758-760.

8. Kovacs, Franz. Uber die angeborene allgemeire Wassersucht der Frucht an der Hand eines Falles. Zentralbl. f. Gynak., 1930, 54, 1948-1954.

9. Goormaghtigh, N. L’oedéme congénital généralisé du nouveau-né; étude anatomopathologique. Ann. d’anat. path., 1925, 2, 413-434.

10. Diamond, Louis K., Blackfan, Kenneth D., and Baty, James M. Erythroblastosis fetalis and its association with universal edema of the fetus, icterus gravis neonatorum, and anemia of the newborn. J. Pediat., 1932, I, 269-309.

11. Clifford, Stewart H., and Hertig, Arthur T. Erythroblastosis of the newborn. New England J. Med., 1932, 207, 105-113.

12. Hellman, L. M., and Hertig, A. T. Erythroblastosis. Am. J. Obst. & Gynec., in press.

Description of Plates


Fig. 1. S—37-292. Placenta of the hydropic variety showing great increase in size and gray, deeply fissured maternal surface. Hellman and Hertig


Fig. 2. S—37-292. Villus from a placenta of the hydropic variety. Great enlargement of the villus is shown. The stroma is of both the hyperplastic and the edematous type. Hematoxylin-eosin stain. X 120.

Fig. 3. Same placenta showing edematous stroma with large multipolar stromal cells and vacuolated Hofbauer cells. Hematoxylin-eosin stain. X 420.

Fig. 4. Same placenta showing hyperplastic stroma with foci of erythropoiesis. Hematoxylin-eosin stain. x 420.

Fig. 5. Same placenta showing vacuolated immature syncytium and _ persistent Langhans’ cells. Hematoxylin-eosin stain. X 420.