1963;32;895 Pediatrics HISTOPATHOLOGIC STUDY OF

FETAL INFECTION IN CHICKENPOX AND ALASTRIM, WITH HISTOPATHOLOGIC STUDY OF THE PLACENTA Pediatrics 1963;32;895

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1963 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Aparecida G. P. Garcia, M.D. Iu,stituto Ferriandes Figueira, Rio de Janeiro, Brasil

T lIE SUSCEPTIBILITY of embryonic and cutaneous lesions at tile time of birth and fetal tissues to viruses is well known, whose mother had chickenpox approxi- and there are innumerable observations of mately one month before delivery. Case 2 congenital virus diseases manifested during was that of a macerated abortion in which intra-uterine life, at the time of birth or on the mother had chickenpox during tile the first days of the neonatal period. fourth month of pregnancy. In Cases 3 and Chickenpox, as a disease conferring a per- 4, both macerated abortions, the mothers manent immunity, is seldom seen in the had abastrim during the fifth and fourth neonatal period, since most pregnant women months of pregnancy. have acquired immunity and transfer it pas- Unfortunately the diagnoses were made sively to the fetus. According to a recent re- retrospectively, so it was impossible to trace view, only 17 cases have been recordedl in the whole history of maternal infection with which cutaneous lesions of chickenpox ap- chickenpox or alastrim during pregnancy. peared before the tenth day of life, with a Our information was limited to the history mortality of 20%. as reported to the obstetricians. We did not In the Quarterly Cumulative Index Medi- make an epidemiologic survey or perform cus (1927 to 1959) only one report was viral studies concerning these cases; how- found of so-called alastrim#{176} in the fetus or ever, in three of them we found fetal lesions newbom.2 However, numerous cases have and inclusions in the decidual cells corn- been recorded3l4 of intra-uterine smallpox patible with the clinical diagnosis. In Case infection and of complications from small- 2, in wihich the mother had had chickenpox, pox vaccination during pregnancy. only nuclear lesions were detected, which, Because of their rarity, four cases of con- in fact, could have been misdiagnosed only genital virus disease, two of chickenpox, as herpes simplex. In Case 3 and 4 charac- and two of alastrim, with heavy cutaneous teristic protoplasmic inclusions of smallpox and visceral lesions, accompanied by un- or alastrim were found. In Case 1 no cell usual and extensive placental lesions, are inclusions were observed, but it is recog- herein reported. nized that absence of inclusions does not preclude the presence of viral infection. MATERIAL The fetal and placental tissues were fixed The present observations concern three in 10% formalin and embedded in paraffin; children (Cases 1, 3, & 4) born at the Mater- the stain routinely used was hematoxylin- nidade Carmela Dutra, in Rio de Janeiro, eosin. and one (Case 2) born at the Maternidade CASE REPORTS Clara Basbaurn included through the cour- Case 1 tesy of Dr. Grelle). Case 1 was that of a 2- day-old premature infant who presented HISTORY: The mother was a 24-year-old white primipara. 11cr last menstrual period occurred in o Dorland’s Medical Dictionary defines alastrim February, 1953; the probable date of delivery as a “specific contagious eruptive fever, resem- was in November. The result of a Wassermann bling smallpox, being probably a mitigated form test was negative. She had mumps during the of that disease.” first days of pregnancy. In September (the seventh

(Submitted for publication, November 6, 1961; accepted April 15, 1963.) ADDRESS: Instituto Fernandes Figucira, Av. Ruy Barbosa, 716, Rio de Janeiro, Brasil. PldrnKrmcs, November 1963

895

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slight edema of epithiehiai cells, with niarginatioii of the chromatin. Ulcerated areas were accompanied by necrosis of the dermis and sometimes of the subcutaneous tissue, vitli chronic cellular infiltration in the dermis. In maii’ organs, large irregular areas of necrosis, sharpl demarcated from tile normal parenchvma with discrete or absent periplwral inflammatory reaction, cxli il)ited deposits of calcium salts in their central portions; in these partially necrotic areas, all the structures had disappeared and few vessels were seen. Iden- tical foci of necrosis were observed in the lungs. liver, kidneys, a(lrenals, thrnus. pancreas. mvocardium, and ititestines (Fig. 2). Necrotic areas in the brain ‘ere numerous; the grossly involved cortical, subcpendvmal, auid basilar structures of the cerebrum were the sites of tissue destruction, in vhich all elements had undergone dissolution. leaving tissue debris, showiiig extensive calcification; the lesions were sharply demarcated. Results of the search for Toxoplasma were negative. Fic. 1. Case 1. Areas of necrosis in the kidney. Case 2

HIsToRY: The niother hid chlicken1)ox in fourth month) SIhe hla(l high fever for 3 days, accom- month of pregnancy and alniost one month after-

I)auli#{128}(lby cutaneous lesions diagnosed as chicken- ward gave birth to a maccrated female fetus, 1)()X by a j)hvsici(Ln. The delivers’ was normal one weighing 520 gm, with a length of 25 cm. month afterward (October). The mother preSeflte(l AUTOPSY Fixnixcs: The macerate(l fetus ‘as cicatricial cutaneous lesions during the puerperium. without external anomalies, with cutaneous lesions The premature female infant weighed 1,700 gm, in the shape of small, irregularly spread, whitish afl(1 the length was 48.5 cm. Lesions of “impetigo” spots, most abundant on the legs and abdomen. were spread over all the cutaneous surface and The visceral alterations were oiil those of macer- scalp. The infant (lid not pass meconium or urine ation. and could not l)e fed because of reflux of the food Microscopy revealerl foci of necrosis in lungs, through the nose. She died 2 days after birth. liver, spleen, adrenals, and kidneys. The l)llCeult1 AUTOPSY FINDINGS: Autopsy revealed a normal was round, 12 cm in diameter, an(l weighed 280 premature infant with deep, ovoid, and well- gm. The cotyledons were not veIl limited and limited cutaneous ulcerations covered by creamy- were whitish in color, with small firm areas com- yellow material or I)V crusts localized on the scalp, parable to “rice seed.” The fetal surface was face, trunk, and limbs. normal; the adnexa showe(l signs of maceration; In the head, vessels of the leptomeninges were the cord ‘as 23 cm in length and t\iste(l. excessively tortuous and congested. Whitish-yellow The villi shoved signs of immaturity and were calcareous areas, irregularly spread on the nervous partially surrounded by heavy exu(late, consisting tissue, were most numerous on the cerebral and of necrotic material, leukoevtes, and nuclear frag- cerebellar cortices and invaded the leptomeninges. ments, which filled the intervillous space (Fig. 3). These were strongly suggestive of lesions produced \lost of the vilhi \sere partially or (ntirelv die- by Toxoplasma. generated; tlie epithlehiuinh had dlisaI)peare(l in In the thoraco-alxlominal cavity, the lungs ad- areas in contact with the aforementioned material. hered to the costa! framework and the diaphragm. Some villi l)r(s(nt((l granulomatous lesions iii the Foul-smelling, purulent liquid was seen in the stroma, whose center was occupied 1)\ a small abdominal cavity, with streaks of fibrin adhereat area of necrosis surrounded by epithelioicl cellS, to the viscera and to the parietal layer of pen- l)y a few giant cells of foreign body type. arid iw toneum. Intestinal loops were adherent and par- round cells. Intercellular deposits of fibrinoid tiallv covered by the omentum. \Vell-himited sinu- material and infiltration of leuikocvtes were seen ous whitish areas, isolated or confluent, were in the decidua. Some decidual cells presentedl in- irregularly spread on the thymus, heart, lungs, tranuclear inclusions, such as an eosinopliilic cen- liver, pancreas, kidneys, and adrenals. (Fig. 1). tral homogeneous mass surrounded by a clear Deep and well-limited ulcers, some of them per- halo, separating it from the nuclear membrane. forated, ere present in the intestines and stomach. pushing the chromatin to the periphery of the Microscopic examination of the skin revealed nucleus (Fig. 4).

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Fic. 2. Case 1. Extensive well-circumscribed areas of necrosis in the mvocardium and kidney, with calcium salt deposits. (x :37)

Case 3 tion. The other organs showed1 only alterations produced by autolysis. hISTORY: ‘lhie mother was 2:3 years old, white, Microscopic examination was partially impaired iara 1 , grad-ida 2, and \Vassermanii negative. The by the degree of maceration of tile viscera. first )regIlanCV was normal, the child was alive Numerous foci of necrosis, without clear limits, aIl(l \‘(ll. For tilt second pregnancy the last with deposits of calcium salts in the center, were menstrual 1)eniOd occurred in July, 1955; the localized in the thymus, lungs, liver, kidneys, prol)ahle date of delivery was given as May, intestines, and adrenals. In the skin tile cells of 1956. In December, 1955 (fifth month), the the superficial layer were covered with calcium nhotlher had! alastrim, at which time fetal move- salts in the nionnecrotic areas. Some perivascular Ifl(’IitS ceased. Delivery was normal 2 montils round-cell infiltration appeared in the dermis. The later. Tile fetus as maccrated, female, and placenta was round, 1 1 cm in diameter, and weighed 450 gm, with a length of 23 cm. weighed 120 gm; the cord was lateraliy inserted. AUTOPSY FINDINGS: Tile maccrated fetus was The cotyledons were pink, with many minute \vitlhOl it external malformations. \Vhitish, well- yellowish areas irregularly spread over the mater- circumscribed, round cutaneous lesions ( 3-5 mm), nal and fetal surfaces, conferring a minute granri- slightiv pronhineilt with depressed centers were lar aspect; the cut surface revealed an identical over all the bod, including the scalp (Fig. 5). aspect; the membranes were thick and dark. The l)rain had lost its normal aspect, due to A few normal appearing villi were in accord nlaceration. The liver was much enlarged, brown- with tile intra-uterine age. Numerous granulom- ish-yellow, with a smooth surface, of normal con- atous lesions, tuberculoid in type, were noted sistencv, and filled the greater part of the abdomen. in the viii or in the conjunctive strands (Fig. 6). Tile spleen was normal. The lungs adhered to the These granulomas had central extensive necrosis, costal fralne\vork and presented whitish, round, very like caseation. They were sharply circum- .superficial areas (2 mm), visible also on cut see- scribed with wavy limits, surrounded by epithelioid

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alive and vell). Her last menstrual period occurred in July 19, 1956; the probable date of delivery was April 19, 1957. During the fourth month of pregnancy the mother had alastrim; 20 days later she had an abortion, delivering a macerated l)abv, male, weighing 180 gin, vith a length of 20 cm. AUTOPSY FINDINGS: The fetus was maccrated with sloughing of the skin in large shreds. Small, whitish, round (5 mm), well-defined dorsal cutanc- oils lesions vere irregularly spread. The viscera showed lesions caused only by maceration; slight hepatomegaly was noted. Microscopic examination, in spite of tile degree of maceration of the viscera, revealed minute and not well-defined areas of necrosis in the lungs, tllymus, kidneys, spleen, adrenals and liver. The placenta was round, 11 cm in diameter, and veiglhed 90 gm; lateral insertion of the cord was noted. The maternal side appeared with a mottled aspect, with minute, intermingled pink and yellow areas. After fixation, innumerable small yellow dots of creamy consistency were seen in tile parenchyma. Microscopic examination, with low-power, showed a uniform aspect of the placenta. The intervillous space was Occupied1 by a heavy cxii- date, consisting of amorphous material and leuko- cytes (polymorphonuclear cells and nuclear debris). The viii had a normal histologic appearance in accordance with the intrauterine age. An increase Ftc. 3. Case 2. Section of the placenta showing of round cells and little areas of necrosis appeared )artially or totally necrotic viii with granulomatous in the stroma. In the decidua, beyond the in- lesions in the stroma. Intervillous space is occu- flammatory exudate, was a deposit of fibrinoid 1)iel l)y iiecrotic material. (x34) material around the cells, many of which had degenerated. In the decidual cells there was cyto- cells, giant cells, histiocytes, and round cells. plasmic inclusion, such as a paranuclear homo- There were frequent groups of partially or totally impaired vilhi, bounded by deposits of fibninoid, some with preserved syncytium and others with I)enil)lleral necrosis, giving the impression that the granuiomatous lesions were located in the intervillous space. A few villi showed calcifica- tioiLs. In the decidua the fibrinoid deposit was ;tl)undaflt, and cell degeneration was remarkable. In these cells cytoplasmic acidophilic inclusion i)odies of various sizes (Guarnieri bodies) limited by a clear space, were found (Fig. 7). Intranuclear inclusions were found equally; they were usually single, oval, and homogeneous masses, surrounded h)y a halo, separating them from the rest of the nucleus, which was sometimes reduced just to its nuclear membrane with a few chromatin dots. ‘[he nuclei and cytoplasmic inclusions were never found within the same cell.

Case 4

hISTORY: [he nhother was 27 years old, gravida Fic. 4. Case 2. Presence of a nuclear inclusion in 5 ( three induce(l ah)OrtiOIhS, one cesarean, child a decidual cell of the placenta. (x 1,000)

Downloaded from pediatrics.aappublications.org at Fiocruz-IFF on May 18, 2011 ARTICLES 899 gefl’Ous corpuscle of irregular size, as described in Case 3. Inside the decidual cell nuclei some structures similar to inclusions were found; however, a badly fixed preparation impaired the in- terpretation of these findings.

COMMENT Four cases of congenital virus diseases were observed (two of chickenpox and two of alastrim), in which maternal infection appeared in different stages of pregnancy, causing fetal abortions (Cases 2, 3, 4) and one preniature delivery (Case 1) with death of tile child 2 days after birth. In all cases identical visceral lesions were seen: focal areas of necrosis, with deposits of calcium salts in the central part, limited by discrete

O1 absent inflammatory reaction and localized in almost all the viscera, including tile nervous tissue. The fetuses were Ill an advanced stage of maceration; this partially impaired tile microscopic examination, although tile foci of visceral necrosis could be easily visual- Fic. 6. Case 3. Group of partially or totally necrotic ized. villi; a granulomatous lesion with a central typical In Case 1 the child survived 2 days, and giant cell. (x405) tile mother presented cicatricial lesions of chickenpox at the time of delivery; the par- mosis, but tile toxoplasma organism was not encilyrnatous lesions were severe, localized found. mainly in the lungs, kidneys, pancreas, and We would like to stress the fact that the brain. The encephalitic process was similar fetal lesions presented tile same characteris- to that produced by congenital toxoplas- tic pattern on gross and microscopic examination, both in the cases of cilickenpox and alastrifll. This type of lesion has been described in 50100 virus diseases such as small-

pox, vaccinia, herpes, aild chickenpox. The current literature emphasizes that the severity of the process is greatest during ultra-uterine life or within the first (laYs after birth. The examillatiOll of tile ilacentas (one case of chickenpox and two of alastrim) showed the presence of lesions that we ilad Ilot had tile opportunity to see described before (Quarterly Cumulative Index Medi- cus, 1927-1959). Tile gross examination showed tiny, yellow, creamy, irregularly scattered areas on tile surface and in the in- Fic. 5. Case 3. \\Tell-defined round and whitish areas with depressed central zones, localized on terior of the placenta. Microscopy’ SllOWed the skin and scalp. granuulomatous lesions of tuberculoid type

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The existence of fetal and pl1ce11tai lesions at the time of birth attest tiie congenital origin of tile infectious process. As Schick has insisted, new studies are necessary to determine which are the dan- gerous diseases for tile fetus. Contact of pregnant women with patients with these infectious diseases, especially viral, must be prevented; tile virus may invade tile maternal circulation and reach tile fetus, even in spite of maternal immunity, as has been proven in cases of chickenpox and German measles.3t SUMMARY Four cases of congenital viral disease are presented. Two cases were of chickenpox (a 2-day old infant and a maccrated abortion) and two were of so-called alastrim, \Vllich is probably mitigated smallpox (maccrated abortions). In all of them one special

Fic. 7. Case 3. An inclusion body (Cuarnieri body) type of lesion was present: focal, irregularly in the cytoplasm of a decidual cell. (x650) sized areas of necrosis, with calcium deposits in the central part, sharply dc- localized in tile villi and the presence of marcated from the surrounding normal par- necrotic material and cellular debris in the enchyma and accompanied by slight or ab- intervilious space, with partial or total de- sent peripheral inflammatory reaction . In struction of tile villous epithelium. The Case 1 (an infant who lived 2 days) such granulomas were easily identified in one lesions were disseminated to all the viscera, case of alastrim (Case 3) and in one of especially the brain; the microscopic aspect chickenpox (Case 2); the microscopic ap- was like that of congenital toxoplasmosis, pearance was the same in both. In Case 4 and the microscopic exam ination revealed (alastrim), the necrotic process prevailed an essentially necrotizing inflalllnlatorv aild tile Illaterial that filled tile intervillous process with extensive calcification and gliai space was particularly prominent. In the reaction. The placenta, examined in two alastrim cases (Cases 3 & 4) there were cases of alastrim and one of chickenpox, cx- seen protoplasmic inclusions in the decidual hibited similar lesions 1)0th on gross and cells of the placenta as oval or irregularly microscopic examination. On the surface shaped bodies (Guarnieri bodies), generally and on the cut section there were flUCFOUS separated from the rest of the cytoplasm by minute, irregularly spread yellowish areas. a clear halo. The nuclear inclusions were The histology showed the presence of characterized by an eosinophilic homogene- tuberculoid-type granulomatous lesions in otis central mass, also surrounded by a clear the villi and extensive areas of necrosis, the halo, often reducing the nucleus to a small intervilious space being occupied by ne- fringe with a few dots of chromatin (Case crotic material and cellular debris. In one of 3). In Case 2 (chickenpox) only nuclear in- tile cases of alastrim (Case 3), there was clusions, with the aspect described above, predominance of the granulomatous lesions;

were visualized. In the chorion and amnion ifl tile other (Case 4), necrosis predomi- there was marked infiltration by histiocytes nated; in Case 2, of chickenpox, beside tile and round cells. granulomatous lesions, there was extensive

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necrosis. In the decidual cells there were 17. Oppenheimer, E. 11. : Congenital chickenpox characteristic inclusions of both the virus with disseminated visceral lesions. BUlL Johns Hopkins Hosp., 74:240, 1944. diseases. Such placental lesions apparently 18. Claudy, W. D. : Pneumonia associated with have not previously been described. varicella : Review of the literature and report of a fatal case with autopsy. Arch. REFERENCES Int. Med., 80:185, 1947. 1. Ehrlich, H. M., Turner, J. A. P., and Clarke, 19. Lucchesi, P. F., and La Boccetta, P. A. R.: M. : Neonatal varicelia: A case report Varicella neonatorum. Amer. J. Dis. Child., with isolation of the virus. J. Pediat., 53: 73:1, 1947. 139, 1958. 20. Eisenhud, M. : Chickenpox with visceral in- 2. Fume, E. : Effects de ha petite v#{233}rolesur les voivement: case report. Amer. J. Med., deux foetus. J. (IC Med., 10:403, 1759. 12:740, 1952. 3. Arzt, L., and Ken, W. : Variola und Fieckty- 21. Cheatam, W. J., Weller, T. H., Dolan, T. F., 1)huIssttl(lien unten bosnischen Ruckvan- and Dower, J. C. : VaricelIa: report of derern aus dem Balkan. Wicn kim. Wschr. two fatal cases with necropsy, virus iso- 26:787, 1913. lation and serologic studies. Amer. J. Path., 4. Lynch, F. W. : Dermatologic conditions of 32:1015, 1956. the fetus with particular reference to variola 22. Vortel, V. : Organone zmeny pni smteln#{233} van- ano vaccinia. Arch. Dcrm. Sph. Chic., 26: celle: Organ changes in fatal chickenpox. 997, 1932. Cesk. P#{233}diat., 13:4, 1958. 5. Marsdan, J. P., and Greenfield, C. R. M.: 2:3. Marsden, J. P. : Metastatic calcification: notes Inherited smallpox. Arch. Dis. Child. 9: on twins born shortly after an attack of small- 309. 1934. pox in the mother. Brit. J. Child. Dis., 27: 6. Schick, B. : Diaplacental infection of fetus 193, 1930. with virus of Cerman measles despite 24. Chaudhuri, K. C. : Vaccinia generalisata. In- immunity of the mother (analogous ob- dian J. Pediat., 2: 111, 1935. servations in smallpox). Acta Paediat. 37-38: 25. Vinh, L. T., et al.: La vanicelie maligne pluni- 563, 1949. viscerale; un cas avec misc en evidence 7. Cramer, A. : Fatal infection with smallpox des foyers de n#{233}crose et des inclusions and vaccination against smallpox. Rev. acidophiles intranucl#{233}aires. Scm. Hop. Med. Suisse Rom., 69:58.3, 1949. Paris, 33: 3989, 1957. 8. Snyder, S. S. : Effect of maternal smallpox 26. Algan, B. : Placental inclusions during corneal vaccination during pregnancy on eye of herpes. Bull. Soc. d’Opht. France: 499, 1949. infants. Amer. J. Ophthal., 34:1713, 1951. 27. Quilligan, J. J., Jr., and Wilson, J. L. : Fatal 9. MacArthur, P. : Congenital vaccinia and vac- herpes simplex infection. J. Lab. Clin. Med., cinia gravidarum. Lancet, 2:1104, 1952. 38:742, 1951. 10. Jelliffe, B. B. : Congenital cataract and mater- 28. Zuelzer, W. W., and Stulberg, C. S. : Herpes nal smallpox. J. Trop. Med., 55:99, 1952. simplex virus as the cause of fulminating 11. MacDonald, A. M., and MacArthur, P.: visceral disease and hepatitis in infancy. Foetal vaccinia. Arch. Dis. Child., 28: Amer. J. Dis. Child. 83:421, 1952. (140): 311, 1953. 29. Feldman, C. V. : Herpes zoster neonatorum. 12. Rao, Y. S. N., and Ratnakannan, N. R., Bala- Arch. Dis. Child., 27: 126, 1952. subramamam, K. S., and Gopalan, S. K. 30. France, V. E., and Wilmers, M. J. : Herpes N. : Smallpox in child aged 3 days. Brit. simplex hepatitis and encephalitis in new- Med. J. 2:1459, 1954. born twins. Lancet, 264:1181, 1953. 13. Zehlwegger, 11.: Smallpox vaccination and 31. Debr#{233},R., Cf al.: Fatal generalized herpes. pregnancy. Helv. Paediat. Acta., 12:563, Arch. Franc. P#{233}diat.12:441, 1955. 1957. 32. Toussaint, P., Schoysman, R. : Herpes gesta- 14. Zellwegger, II.: Vaccination antivaniolique et tionis: #{233}tudeanatomoclinique des lesions grossesse. J. Med. Libanais, 10:118, 1957. foetales. Arch. BeIg. I)erm. Syph., 13:149, 15. Schleussing, H.: Nekrosen in Leber, Milz und 1957. Nebennieren bei nicht vereiterten Van- 33. Tout#{233}e, F.: La maladie herp#{233}tique du zeilen. Verhandl. Deutsch. Path. Gesellsch nouveau-ne. Gaz. Med. Franc., 64:1729, 22:288, 1927. 1957. 16. Johnson, H. N.: Visceral lesions associated 34. Warkany, J.: Etiology of congenital malforma- with varicehia. Arch. Path., 30:292, 1940. tions. Adv. Pediat., 2:48, 1947.

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