The Blood Chemistry in Erythroblastosis Fetalis

THE BLOOD CHEMISTRY IN BRYTHROBI;ASTOSIS FET Al~IS REPORT OF THREE CASES WITH ABNORMAL FINDINGS ARTHUR WEINBERG,

M.D.,

PAR ROCKAWAY,

N. Y.

(From the Department of Obstetrics, Sinai Hospital, Baltimore, Md.)

is still an obscure enough disease to

RYTHROBI;ASTOSIS fetalis merit reporting any new findings which might throw light on its E pathogenesis, symptomatology, or treatment. With this in mind I wish to report three proved <>ases with distinctly unusual blood chemistry findings. In a brief review of the literature including the elassieal reports of the disease,I- 3 I found no referenee to unusual findings in the blood urea, blood uric acid, and blood ehloridt' values. Moreover, the conelnsions as to the serum protein values are not in agreement. The clinical, hematologic, and pathologic pictures are fairly uniform in all cases, but except for the bilirubin determinations the other chemical determinations seem to have been overlooked. The reason for this is probably the technical difficulty in obtaining sufficien1 blood from newborns for eomplete analysis. In addition possibly wmal ehanges were not suspected or present. REPORT OF CASES

Thf' following thrrr rases wPre all ~e•m at the 1-\inai Hospital, Baltimore, Maryland: '!'he sixth ge~tational prorlu~t of Mrs. E., aged 31, whOHE' previous pre~;rnancies tPrminated as follows: ( J) Normal full-term parturition at Sim1i Hospital. Child alive and well aged 11 years. (2) Full-term parturition, chili! developed jaundice and died at Johns Hopkins Hospital at the age of one month. No autopsy re<'m·d was obtained; the diagnosis was icterus gravis. This was in 1926 before erythroblastosis was recognized as a clinical entity. (3) Full-term stillborn at Sinai Hospital; cause of death not determined. ( 4) Premature infant that lived three days. (5) Full-term stillborn, intranatal death. This labor was induced by 25 gr. of quinine. This was thought to be a possible cause for intrauterine death. During the pregnancy now under consideration a thorough study for the cause of the fetal deaths was made. Diabetes mellitus was excluded by a normal blood sugar and a normal glucose tolerance test as well as by the absence of glycosuria. Syphilis was eliminated by a negative Wassermann and Kahn reaction. However, on the advice of the syphilologist one emme of the antisyphilitic therapy was given in the early part of pregnancy. The patient exhibited no evidence of either early or late toxemia. In view of the patient's story that towards the end of each preceding pregnancy, she had noticed that in the last month the fetal movements became less pronounced and finally ceased, it was decided to admit her for induction of labor, without quinine, three weeks before term. Labor was induced and the delivery was normal. At birth the child cried immediately and respiration was established spontaneously. The vernix was scant and white and the placenta was normal in size and consistency. The characteristic thick yellow vernix caseosa was not present. The delivery was at night and in the artificial light no jaundice was noted. Eight hours after delivery the chi1d developed jaundice. Hematologic study revealed an erythroblastic anemia with characteristic :findings. The hemoglobin was 90 per cent, red blood count CAsE ] .~Baby E.

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BLOOD CHEMISTRY IN ERYTHROBLASTOSIS FETALIS

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:J,350,000 per c.mm., with a color index of 1.3. The acetic acid residue showed 80,000 nucleated cells of which 45,600 were nucleated red cells and 34,000 were leucocytes. The Schilling differential showed 15 per cent early white cells, mostly myelocytes and mestamyelocytes, 45 per cent polymorphonuclear neutrophiles, 30 per cent lymphocytes, 8 per cent monocytes, 2 per cent basophiles. The nucleated red cells were macronormoblasts and normoblasts. The red cells in the smear showed

Fig. 1.-Baby E. Erythroblastosis with icterus gravis. Section of the liver showing foci of erythroleucoblastic activity. Deposits of hemosiderin were numerous.

Fig, 2.-Erythroblastosis with icterus gravis. Section of thymus showing typical macronormoblasts growing in an extramedullary focus of blood production. anisocytosis with predominance of macrocytes. The clotting and the bleeding time were within normal limits. The platelets were moderately reduced. The fragility test was normal. The Wassermann test was negative and the roentgenologic examination of the long bones failed to show syphilis. The icterus index was 100, and the van den Bergh hi-phasic. The gastric contents (vomitus) revealed bilirubin, ruling out biliary obstruction. The urine had a trace of bilirubin and urobilin. The stools were positive for bilirubin and urobilin.

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AMF:RICAX .JOU RNAL OF Oll:-;TETRIUS ,\:\'D «Y N ECOLOUY

'l' he ehild had an e>nla rg·l'o] s plt' en and liver and, in a f e w d a ys, .tun' lopcd ri gidi ty of' ne<'k awl liml•s. I Juring rh,• f olltllr ing· eight day~ l:h·· :jaun•li re l>t>eame more inHow ever . th e wn~e , pallor a PllP rl, and tilt' anemi a ht•<'aJJH' pro gTPR~i vel _, . \V O l' ~'' · nudeated rl'd "''lis gra•l ually '""'': tl~ l< · lt-~ s l!UIItPl'!Jll~ and l•y tli P (l>nl'h day 1rere entirel y ahsc•nt. At this tinw the il't PI'U' iwlo- ~ w:1 ~ J.) !l awl til•• un•a 1ra ~ :2 0 11 lllg'. per •·Pnt. 'The r.hihl wa ~ 1reat ed wi t·h n •·.ow·<•ntrat ...l fonnul a , da il:" •·.ly""" ,,f ;) pN eent glu<'ose, anu repeate.J blood t ra ns f'us·iOJl:', hut IHI ti!lo' f'lf'V C'H t h is in the li ve r, SJ•lern, kidney, panen•H.s, adrenal~. thym us. pi t ui t a ry. anix \I'C' e k H t ho lnother tlt' l't•lopetl erl ema, antl dyspnea. Thi s was so marke•l th a t we t· onsitlNetl t.lw possibility of i nwrruption. The mine showed a one-plu" alb1!11 1i u. The phcnol sulphonehy
Fig. 3.-Seeti o n uf tht! bon e

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f' h0·win;.;- a bnonn a l

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ur

t·l·ythrobla s t ~.

phthalein test showed 65 Jler cent reeowry in t.\1·o hours. The hluod t;hemistry was essentially normal: U rea ~4 mg. per cent, ehloride 371 mg. per cent, and total serum protein 7.8 mg. per rent, with an albumin globulin ratio of 2. The uric. acid was elevated to 5. 3 m g . p er cent. 'l'he maternal Wassermann r eac tion was negative. The hydramnios and edema f ailed to respond to r'onsen ·a.tive trea tment and t he pregnaney was interrup ted at thirty-s ix weeks b~· medical includion f ollowed by a rtificial puncture of the membranes. Labor was uneomplieated nn d t he se<"ond stage was terminated by an episiotomy and low f orreps deliYery of a live f t:n na le l'hild which weighed 6 pound s 12 ouu('es. The general eondition of the ehila was poor. The temperature was !lli ° F ..• th e heart aetion slow and in<• gula1·, ery wenk, and respirations slow and shallow. J.t. w a~ quite diffieult to resuscita te and int.ratracheal aspiration, water bath~ awl artifkial r<'spiration, follow ed hy intratnwheal insufflation with a resuscitator Wt>re ner cssary hrfor<' th e in f ant was breathing regularly. The infant kept expedora t·ing· f roth y ~pu tum . Physically the inf an t presfmt.ed gener alized ana sa rca in1·olving esp.,eially the face, hands, feet, and r hest. 'l'hc ~ki n \\' a~ pale awl ryanoti r . The heart was not enlarged and there were no murmm· ~. The chest present ed diffu se moist rales. The abdomen presented p'hysica l signs of a scites. The liver, spleen, and kidneys were not palpable,

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BLOOD CHEMISTRY IN ERYTHROBLASTOSIS FETALIS

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'l'here was marked vulval edema anti the extremities had pitting edema. The placenta was large and friable but the vernix was normal in color and consi~tEmcy. A hema· tologic study revealed a macroeytic anemia. The l1emoglobin was 75 per cent. The red bloml count 2,960,000. 'l'he color index was therefore 1.25. The total acetic acid resistant count was 7,600 with 34 per cent of them nucleated red cells. The Schilling differential count showed 47 per eent polymorphonuclears, 44 per eent lymphocytes, 1 JWr rent monorytes, 6 per cent myelocytes, and 2 per rent juYeniles. The urine was scant, with one·plus albumin and 5·6-plus cells per high power field. The blood chem· istr;v was again abnormal. The mea ·was 40 mg. per cent and the uric !Hoid 1'1.5 mg. per cent. The e.hlorides were 14~ mg. per eent. The serum protein was i.4 per cent with an A/G ratio of 4.:1. The blood \\'assermann reaction was negative as were the x·rays of the long bones. ';'he infant was placed in a heated crib with continuous pure oxygen supply inter· rupted by frequent carbon dioxide inhalation~. 1'-1wle blood was given intramu~c;u· larly but the infant bel'ame gradually worse and died within twelve hours. A few hours before death, 0.5 c.e. of mereupurin was given intramusculal'ly but failed to exert any manifest artion before death. The autopsy revealed marked ana· sar<'tt with particular edema of tlw face aml the ascites, and hydrothorax. ThP viseera were pale and edematous but asiu<·oblastic vari<>ty in the liver, ~pleen, thymus, pancreas, adrenals, lymph nodes, and bone marrow. 'rhis ease of hydror's is noteworthy chiefly because of the potential toxemic status of the mother combined with the unu~ual hlood clwmi~tQ' of the offspring. CASE :i.-Baby F. First pregnancy. Jlelivered normally at term, weighed 7 pounds 0% ounces, and was horn jaundiced. The amniotic fluid was bile stained, ancl the vernix was thkk anti yellow but the placenta was normal. Physical exam· inatlon revealed splenomegaly in addition to ~evere icterus. Within the twenty-four hours after birth the <·hild dm·eloped ;lyspnea, eyano~is, and refused nourishment. A few hours later the child had marked lwmatemesis and moderate vaginal bleet1ing. 'rhe blood eount revealed a :re anemia with the color index slightly above one, the hemoglobin being 25 p<'r •·ent fm•l the reAl hlood count l,:WO,OOO per c.mm. Smear and white count were not ohtaine
In all three cases of erythroblastosis presented there were abnormal blood chemistry findings varying from slight nitrogen retention to uremia. The nonprotein nitrogen and blood urea were elevated in all three cases, and the blood uric acid was elevated in the first two. '!'his is in :favor of renal insufficiency as a significant faetor in the :fatal cases, at least, since all these three infants died. The six kidneys examined pathologically from these three cases failed to exhibit any organic changes of nephritis or nephrosis. It may be that in newbOl'ns, renal insufficiency may result from functional changes incident to a severe anemia, or secondary to an intercurrent infP<'tion or preceding death from erythroblastosis.

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AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY

As regards the pathogenesis of erythroblastosis a suggestion as to the underlying differenc•f' in the clinical pictures of icterus gravis, hydrops feta1is, and congenital anemia is found in contrasting the clinical pathologic findings in these eases. In hydrops, although the nucleated blood cells in the peripheral blood were only moderately increased, the foci in the viscera were exceedingly plrntiful, thus favoring the view that in hydrops fetalis the pathogenesis lies either in overgrowth of immature forms, or a failure of maturation of erythroc~'tes. However in icterus gravis in which the nuf'leat0d red cell count is higher, and the foci in the viscera less plentiful the etiology lies in the delivery of these immatlne forms to tlw (~irenla1 ion with resu11 ing inerNtse in destruction. Hellman and Hertig/ in a ::;tudy of 1:1 autopsies on infants who died of hydrops fetalis and (i 011 infants who died of icterus gravis, also found more extramedullary ct~'thropoiesis in the fornwr group. The reason for thP spastieity in nuclear ieterus has never been fnlJ:r~ explained even though pigmentation of the central nervous system has been obsern•il. In Case 1, the infant developed spasticity and rigidity of the neek and limbs assoeiated with azotemia. This uremia associated with acidosis may hr responsible for the rigidity of the neck and limbs. This typp of spasticity is ver,v often :-:e€·n in so-ealled nuclear icterus, the outstanding feature of ~whieh is the pigmentation of the cerebral nervous system, particularly the large ganglia. It is suggested that the azotemia associated with ictems gravis may he responsible for the central nervous system symptoms frequently found in nuclear icterus. In explanation of the edema, in erythroblastosis \Vith hydrops fetalis some authorities have steessed the albuminuria, decrease in total serum protein, and reversal of the A/<+ ratio as the cause. In Case 2 the albuminm·ia was slight, the serum proteh1 nonnal, and the A/G ratio accentuated strongly suggesting another cause for the edema. The total urinary output was diminished and this oliguria combined with azotemia speaks for renal insufficienry as the cause of the edema. The low blood ehloride is best explained by the loss of chloride with the edema, anasarca, and effusion fluids. The low chloride value is seen also in cases of nephritis with edema and in easrs of nephrosis. CONCLUSIONS

1. Azotemia is a frequent complication in severe cases of erythroblastosis of all types, and when present makes the prognosis much worse. 2. This azotemia may be the responsible factor in the central nervous system symptoms in nuclear icterus. 3. Renal insufficiency, per se, :md not albuminuria and decrease in serum protein, is the more probable cause of universal edema of the newborn. 4. In the absence of signs of acute nephritis, mercurial diuretics along with blood transfusions and lyophile (concentrated human serum) seem to be indicated in treating the edema. Sl:l\llVIARY

Three fatal cases of erythroblastosis fetalis are presented, one with icterus gravis, one with hydrops fetalis, and one with congenital anemia,

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PRECOCIOUS PUBER'l'Y DUE TO OVARIAN CYS'r

485

all of which showed abnormal blood chemistry: azotemia, which is therefore regarded as an unfavorable prognostic sign. The author wishes to thank Dr. Daniel Sondheimer, resident pathologist at Sinai Hospital, Baltimore, Md., for the pathologic examinations and for helpful suggestions in the preparation of this paper.

REFERENCES

(1) Clifford, S. H., and Hertig, A. 1.'.: New England J. M. 207: 105, 1932. (2) Blackfan, Kenneth D., Diamond, L. K., and Baty, J. M.: .T. Pediat. 1: 269, 1932. (3) Astrachan, Morris: Am. J. Dis. Child. 53: 137, 1927. (4) Hellman, LO'Uti8 M., and Hertig, A1'thur T.: AM. ,T. 0BST. & GYNEC. 36: 137, 1938.

PRECOCIOUS PUBERTY DUE TO AN OVARIAN CYST IN A FIVE-YEAR-OLD GIRL WILLIAM

F.

MENGERT,

M.D.,

IowA CITY, IowA

(From the Department of Obstetrics and Gynecology, The State Um:versity of Iowa J years (Hospital Number E 6088), was first seen July 13, 1935, N . A.,withagedthe fivehistory of considerable breast development during the previous two

months. On the day before consultation, the child while sitting on the toilet, announced, ''Cherry juice is running down my legs.'' On inspection definite blood mixed with mucus apparently coming from the vagina, could be seen on the inner surface of each thigh. Subsequently a study of the visual 1ields and a roentgenogram of the sella turcica were done and revealed no abnormalities. The breasts were deilnitely enlarged (Fig. 1, A) and the parenchyma was nodular and shotty. There was bloody mucus with a typical menstrual odor smrounding the vulva, and the external genitalia, although small and in proportion to the child's size, presented such adult characteristics as brownish pigmentation and well-developed and sharply-defined labia minora. In addition, the vaginal mucosa was not only unlike that of a prepuberal child but also was thrown into definite folds resembling rugae. There was no well-defined axillary or pubic hair although on close inspection a few scattered hairs could be seen on the mons veneris. Rectobimanual examination was done under anesthesia the following morning. The uterus was enlarged almost to the size of that of an adult virgin. There was a cystic, symmetric mass, the size of a golf ball, in the left adnexal region, but nothing was palpable on the right side. Biopsy of the vaginal epithelium taken at this time showed (Fig. 2) hyperplastic mucosa with a stratified, considerably thickened, squamous epithelium slightly cornified in some areas, and with a papillated basal layer. E:xploratory laporotomy was performed on July 16, 1935. The right ovary was small, the size of a navy bean, and its surface was smooth, presenting no follicles. It was the typical ovary of a child. The left ovary was replaced by a smooth, glistening cyst 4 to 5 em. in diameter (Fig. 3). Both tubes were extremely long and tortuous and with the uteruR were approximately of adult size. In fact, with the except'lon of the right ovary, all of the intra-abdominal genitalia presented adult characteristics. Careful palpation of each kidney and suprarenal area revealed nothing unusual. Left salpingo-oophorectomy with cornual excision and appendectomy were performed. 'I'he report of Dr. H. P. Smith is as follows: "The left ovarian mass measures two and a half by four centimeters in diameter. The surface is smooth and beneath it can be seen several cysts three millimeters in diameter. On section several larger cysts are found. They are lined by a smooth yellow membrane. Microscopically the lining of the cysts is composed of polyhedral cells several cells in thickness. Some resemble granulosa cells; others have vacuolated cytoplasm, like that of lutein ceJls. The stroma between the cysts is of the normal mature type.