Pediatric and Developmental Pathology 18, 331–334, 2015 DOI: 10.2350/15-01-1603-CR.1 ª 2015 Society for Pediatric Pathology
Coxsackie Virus A16 Infection of Placenta with Massive Perivillous Fibrin Deposition Leading to Intrauterine Fetal Demise at 36 Weeks Gestation WEIMING YU,1,2* RAYMOND TELLIER,3
AND
JAMES R. WRIGHT JR1,2
1
Department of Pathology & Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Calgary Laboratory Services, Calgary, AB, Canada 3 Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, and Provincial Laboratory for Public Health, Calgary, AB, Canada 2
Received February 10, 2015; accepted March 26, 2015; published online March 31, 2015.
ABSTRACT Massive perivillous fibrin deposition (MPFD) is an uncommon placental disorder, associated with significant fetal morbidity, mortality, and recurrence; its etiology is unknown. We describe a 31-year-old mother, diagnosed with Coxsackievirus infection and hand-foot-and-mouth disease at 35 weeks gestation. Ultrasound at 35 weeks revealed a normal fetus and placenta. One week later, the mother experienced decreased fetal movement and ultrasound demonstrated intrauterine demise. The autopsy showed mild, acute pericarditis and hypoxic-ischemic encephalopathy. Placenta examination showed MPFD involving 80% of the parenchyma. Molecular viral analysis and serotyping showed Coxsackie A16 virus. The mother had an uneventful pregnancy 15 months later. Coxsackievirus infections in pregnant mothers are often asymptomatic. Transplacental Coxsackievirus infection is very rare but is associated with spontaneous abortion, intrauterine demise, or serious neonatal morbidity. Mild, nonspecific histologic changes have been reported in the placenta. To our knowledge, this is the first report of MPFD associated with Coxsackievirus infection. Key words: Coxsackievirus A16 infection, hand-footmouth disease, intrauterine fetal death, massive perivillous fibrin deposition
INTRODUCTION Massive perivillous fibrin deposition (MPFD), also known as gitterinfarct [1], is a rare placental disorder occurring in 0.028% to 0.5% of deliveries [2,3]. It is characterized by the accumulation of a combination of polymerized serum fibrin and trophoblast-derived extra*Corresponding author, e-mail: [email protected]
cellular matrix products, which encase chorionic villi throughout the placenta. The fibrinoid material surrounding the chorionic villi impairs transplacental gas and nutrient exchange. Maternal floor infarction (MFI) is considered a related placental disorder in which the involvement is limited to the maternal interface, and some pathologists consider these spectrums of the same process. The etiology is unclear. Massive perivillous fibrin deposition is associated with significant fetal morbidity, mortality, and recurrence. Further study is critical to elucidate its causes, to establish suitable intervention strategies to reduce the severity, and to prevent recurrence. We describe a case of a 31-year-old mother who had recent hand-foot-and-mouth disease as well as Coxsackievirus A16 infection of the placenta and MPFD, which resulted in intrauterine fetal death at 37 weeks gestation. To our knowledge, this is the first report of placental MPFD associated with Coxsackievirus infection.
CASE REPORT The mother is a 31-year-old G2, P1, T1, L1 woman. Her early pregnancy was unremarkable; obstetrical ultrasound examinations at 7 and 18 weeks, respectively, revealed a normal pregnancy with a single viable fetus. At 32 weeks gestation, the mother presented with flu-like symptoms and a sore throat. At 35 weeks, she developed a sinus infection with fever and a productive cough, followed by blisters on her oral mucous membranes, a maculopapular rash, and small blisters on the palms of her hands and the soles of her feet, and eventually extending to her chest. Her serum test for parvovirus B 19 IgM was negative but IgG was positive; cytomegalovirus (CMV) IgM was negative, and IgG was positive. Serum IgM antibody to rubella, toxoplasmosis, and syphilis were all negative. Fetal ultrasound at 35 weeks, 3 days,
Figure 1. The placenta revealed diffusely irregular strands and clumps of pale-gray induration throughout the placenta, with more than 80% of the disc volume involved. A color version of this figure is available online.
revealed a normal, single fetus in cephalic presentation with a normal fundal placenta and normal amniotic fluid. At 36 weeks, 3 days, of the pregnancy, the mother experience decreased fetal movement for 1 day, and ultrasound examination demonstrated intrauterine fetal death. A stillborn, female fetus was spontaneously delivered via vagina at 36 + 4 weeks gestational age. Consent for a complete autopsy was obtained. At autopsy, the female fetus was grossly unremarkable. The body weight (2540 g) and measurements were consistent with 35 weeks gestational age. The brain and liver weight ratio was 3.72. Microscopic examination showed a focal, mild, acute inflammatory-cell infiltrate limited to the epicardium, but no myocarditis. Blood culture results were positive for enterococcus faecalis, which was attributed to contamination at autopsy. Neuropathologic examination showed fetal hypoxic-ischemic encephalopathy with ischemic, red, neuronal changes in the dentate nucleus, superior colliculus, and pons; apoptotic bodies were present in the subiculum and pons. There was no evidence
of encephalitis. The placenta was oval shaped (17 3 16 3 2.5 cm) with a trimmed weight of 324 g (reference range, 441 g; 10th percentile, 320 g). The placenta showed macroscopically diffuse involvement with irregular strands and clumps of pale-gray induration throughout; more than 80% of the disc volume was involved (Fig. 1). Histologic examination showed diffusely transmural massive perivillous deposition of eosinophilic fibrillar and lattice-like fibrinoid material in the intervillous space (Fig. 2a). The fibrin tightly encased the villi, which showed variable stromal hypovascular/sclerotic changes and variable denudation of the surface trophoblast (Fig. 2b). Gomori trichrome stain highlighted brilliantred fibrinoid material in the intervillous space, indicating a fibrin-type fibrinoid [5], extending from the maternal surface to fetal surface and encasing 80% of the villi in all 8 random sections. There were also patchy aggregates of CD68+ histiocytes within the intervillous spaces, strongly suggestive of chronic histiocytic intervillositis (Fig. 3a,b). Placenta and umbilical cord tissue was submitted for polymerase chain reaction and reverse transcriptionpolymerase chain reaction molecular viral analysis, which was positive for enterovirus but negative for CMV, respiratory syncytial virus, parvovirus, herpes simplex, influenza, and parainfluenza viruses. Molecular serotyping by sequencing and analyzing a segment of the VP2 gene was performed, as previously described [4], and showed the enterovirus to be Coxsackie A16. Fetal lung, liver, heart, and brain submitted for virus detection were all negative. After 15 months, the mother had a subsequent, uneventful pregnancy and a live-born, healthy baby was delivered at 39 weeks gestation; the placenta was not submitted for pathology examination.
DISCUSSION Coxsackieviruses are nonenveloped viruses that have a positive single-strand RNA genome and belong to the genus Enterovirus. Coxsackie A and B viruses were initially defined by their capacity to cause flaccid or
Figure 2. (a) Diffusely massive perivillous deposition of lattice-like, fibrinoid material in the intervillous space, extending from the maternal surface to the fetal surface, encasing more than 80% of the villi. (b) Fibrinoid-encased hypovascular and sclerotic villi showing surface trophoblast damage and loss. A color version of this figure is available online.
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Figure 3. (a) Multifocal aggregates of intervillous histiocytes are strongly suggestive of chronic histiocytic intervillositis. (b) Patchy aggregates of CD68+ histiocytes are shown within the intervillous spaces. A color version of this figure is available online.
spastic paralysis, respectively, in newborn mice. In all, 23 serotypes of Coxsackie A and 6 serotypes of Coxsackie B have been described. Like all enteroviruses, most infections are asymptomatic. Different serotypes of Coxsackie A viruses have been associated with exanthemata and enanthemata (and classically with hand-foot-mouth disease) and with other diseases, such as aseptic meningitis and respiratory diseases. Different serotypes of Coxsackie B viruses are causative agents of diseases, such as myocarditis, respiratory infections, pancreatitis, and have been associated with cases of acute onset of type I diabetes [6]. Pregnant women are frequently exposed to enteroviruses. Coxsackievirus infection in pregnant women does not readily cross the placenta to cause fetal disease, but vertical transmission can occur in the perinatal period [15]. However, rare cases of transplacental passage have been documented to cause variable morbidity and mortality in fetuses and neonates. Some fetuses and newborns are not affected, despite the presence of Coxsackievirus infection in the placenta [7,8]. Two reported cases of first-trimester Coxsackie A16 placental infection were associated with spontaneous abortion at 7 and 12 weeks, respectively [7]. Intrauterine fetal demise with myocarditis, pericarditis, and meningoencephalitis in late pregnancy has been documented. Seven cases of intrauterine fetal-acquired Coxsackie infection causing severe respiratory failure and central nervous system developmental delays in newborn infants have been reported [8]. Affected live-born neonates can present with severe sepsis, hypotension, leucopenia, thrombocytopenia, and disseminated intravascular coagulopathy; severe, long-term neurologic sequelae with widespread cortical necrosis have also been described [8]. Coxsackievirus infection associated histologic changes in the placenta are not well studied. A few studies have described mild and nonspecific histologic changes, including Hofbauer cell hyperplasia, focal chronic villitis, focal hemorrhagic endovasculitis, and focal calcification [8,9]. Massive perivillous fibrin deposition and MFI are closely related disorders with considerable clinical and
pathologic overlap but unknown pathogeneses. Proposed hypotheses include maternal autoimmune disorders, cytotoxicity by pregnancy-associated major basic protein produced by abnormal X-cells, a genetic cause (because of the high recurrence rate), or a manifestation of latent herpes simplex infection [3,10,11]. Co-occurrence of MPFD and chronic histiocytic intervillositis has been reported [10]. In our current case, there was an element of this latter entity (Figure 3a). Placental fibrinoids are extracellularly deposited, histologically glossy eosinophilic materials found in every normal placenta. Immunohistochemical and ultrastructural studies have analyzed the composition of fibrinoids; 2 types of fibrinoids have been described [5,12,13]. Fibrin-type fibrinoid is derived mainly from a maternal blood product, together with other molecules and a degenerative process. Matrix-type fibrinoid is a secretory product of extravillous trophoblast cells containing laminins, collagen IV, heparin sulfate, oncofetal fibronectins, vitronectin, and glycosylated molecules. The matrix-type fibrinoid embeds the secreting cells and regulates trophoblast invasion by specific interactions with cell-surface molecules. On hematoxylin-eosin (H&E) stain, both fibrinoid types have similar eosinophilic appearance, but the matrix-type fibrinoid contains clusters of extravillous trophoblast cells, whereas fibrin-type fibrinoid is devoid of those cells [5,11]. With Gomori trichrome stain, fibrin-type fibrinoids usually stain red or orange, whereas the matrix type usually stains aniline blue or lightly green. Several studies have suggested that the deposition of fibrinoid is a secondary response to trophoblastic cell injury. The chorionic villi in our case showed the presence of a fibrin-type fibrinoid encasing the villous surfaces denuded of syncytiotrophoblast, which could suggest that Coxsackie A16 caused degenerative changes in the syncytiotrophoblast cells. We cannot rule out the possibility that the placental Coxsackie infection was coincidental to the fetal demise rather than causative, especially because the fetal tissue results were negative. However, because it is known that transplacental passage of Coxsackievirus is rare [15], in our case, perhaps, the maternal infection simply
INTRAUTERINE COXSACKIE VIRUS AND MPFD LEADS TO FETAL DEMISE
333
precipitated the fibrinoid deposition, and MPFD was the direct cause of demise. This analysis was supported by the absence of autopsy findings, except for acute ischemic changes in the brain, which were probably due to placental insufficiency caused by acute-onset MPFD. Interestingly, there was no evidence of intrauterine growth retardation (IUGR) in our case because fetal measurements, both on prenatal ultrasounds and at autopsy, were appropriate. This supports the premise that the onset of MPFD was acute and its onset was closely associated with the Coxsackie infection, as a morechronic process would likely have caused IUGR. In fact, most cases of MPFD are associated with IUGR [2,3,10]. The pathologic diagnosis of MPFD is subjective because there are no standardized criteria for the diagnosis. Deposition of perivillous fibrinoid is a normal phenomenon, occurring in every placenta, and the amount increases as pregnancy advances. Quantitative diagnostic criteria for MPFD could improve diagnostic reproducibility. Correlation of macroscopic and microscopic examination is essential in differentiating MPFD from nonspecific changes. Fox and Sebire [14] indicated that the normal placenta can withstand a loss of up to 30% of functioning villi without any evidence of adverse effects; therefore, the diagnosis of MPFD should be reserved only for those placentas in which more than 30% of villous parenchyma is obliterated by fibrin. Other authors apply the diagnosis of MPFD when more than 30% of the villi in the central region of the placenta are encased in fibrinoid material or more than 40% of the chorionic villi are involved. Weber and colleagues [10] suggested the diagnostic criteria of more than 50% of the placenta parenchyma obliterated by fibrin. The average placental area involved for the diagnosis is 50% by Bane and Gillan [3] and ranges from 20% to 90%. Several authors have emphasized that a major impediment to the diagnosis is the variability and stringency of diagnostic criteria. The extent of perivillous fibrin deposition in the placenta in our case was greater than 80%, both in gross examination and microscopic analysis, in all 8 random sections of the placenta parenchyma, which meets with the strictest diagnostic criteria for the disease. Although MPFD is known to be associated with a high risk of recurrence in subsequent pregnancies, in our case, the mother had a normal-term pregnancy with a healthy baby delivered 15 months after the onset of MPFD. The result suggests that etiology and pathogenesis of MPFD are heterogeneous. Clearly, MPFD associated with Coxsackievirus infection does not necessarily recur in a future pregnancy. In conclusion, we describe a case of placental Coxsackievirus A16 infection in a 31-year-old mother, who had recent hand-foot-mouth disease. She presented with MPFD and intrauterine fetal death at 36 weeks
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gestation. To our knowledge, this is the first report of MPFD being associated with Coxsackievirus infection. In view of the clinical course of our case, the time from initial, mild, flu-like symptoms in the mother until intrauterine fetal death was only few weeks, awareness of this possible devastating complication of Coxsackievirus infection in pregnancy should be raised among obstetricians, neonatologists, and pediatricians, thus, enabling them to make appropriate clinical decisions and provide adequate counseling to parents. Immediate induction of the labor or caesarean section should be considered. REFERENCES 1. Waters BL, Ashikaga T. Significance of perivillous fibrin/oid deposition in uterine evacuation specimens. Am J Surg Pathol 2006; 30:7602765. 2. Uxa R, Baczyk D, Kingdom JC, Viero S, Caster R, Keating S. Genetic polymorphism in fibrinolytic system of placentas with massive perivillous fibrin deposition. Placenta 2010;31: 4992505. 3. Bane AL, Gillan JE. Massive perivillous fibrinoid causing recurrent placental failure. BJOG 2003;110:2922295. 4. Pabbaraju K, Wong S, Chan EN, Tellier R. Genetic characterization of a Coxsackie A9 virus associated with aseptic meningitis in Alberta, Canada in 2010. Virol J 2013;10:93. 5. Kaufmann P, Huppertz B, Frank HG. The fibrinoids of the human placenta: origin, composition and functional relevance. Ann Anat 1996;178:4852501. 6. Pallansch M, Roos R. Enteroviruses: polioviruses, coxsackie viruses, echoviruses and newer enteroviruses. In: Fields Virology, 5th ed., Knipe DM, Howly PM, eds. Philadelphia: Lippincott Williams and Wilkins, 2007. 7. Ogilvie MM, Tearne CF. Spontaneous abortion after hand-foot-and mouth disease caused by Coxsackie virus A16. Br Med J 1980;281: 152721528. 8. Euscher E, Davis J, Holzman I, Nuovo GJ. Coxsackie virus infection of the placenta associated with neurodevelopmental delays in the newborn. Obstet Gynecol 2001;98:101921026. 9. Batcup G, Holt P, Hambling MH, Gerlis LM, Glass MR. Placental and fetal pathology in Coxsackie virus A9 infection: a case report. Histopathology 1985;9:122721235. 10. Weber MA, Nikkels PG, Hamoen K, Duvekot JJ, de Krijer RR. Co-occurrence of massive perivillous fibrin deposition and chronic intervillositis: case report. Pediatr Dev Pathol 2006;9: 2342238. 11. Benirschke K, Kaufmann P, Baergen RN. Pathology of the Human Placenta, 5th ed. New York: Springer, 2006. 12. Frank HG, Malekzadeh F, Kertschanska S, Crescimanno C, Castellucci M, Lang I, et al. Immunohistochemistry of two different types of placental fibrinoid. Acta Anat (Basel) 1994;150:55268. 13. Vernof KK, Benirschke K, Kephart GM, Wasmoen TL, Gleich GJ. Maternal floor infarction: relationship to X cells, major basic protein, and adverse perinatal outcome. Am J Obstet Gynecol 1992; 167:135521363. 14. Fox H, Sebire NJ. Pathology of the Placenta, Major Problems in Pathology, 3rd ed. Philadelphia: Saunders Elsevier, 2007. 15. Amstey MS, Miller RK, Munegus MA, di Sant’Agnese PA. Enterovirus in pregnant women and the perfused placenta. Am J Obstet Gynecol 1988;158:775.
Coxsackie Virus A16 Infection of Placenta with Massive Perivillous Fibrin Deposition Leading to Intrauterine Fetal Demise at 36 Weeks Gestation WEIMING YU,1,2* RAYMOND TELLIER,3
AND
JAMES R. WRIGHT JR1,2
1
Department of Pathology & Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Calgary Laboratory Services, Calgary, AB, Canada 3 Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, and Provincial Laboratory for Public Health, Calgary, AB, Canada 2
Received February 10, 2015; accepted March 26, 2015; published online March 31, 2015.
ABSTRACT Massive perivillous fibrin deposition (MPFD) is an uncommon placental disorder, associated with significant fetal morbidity, mortality, and recurrence; its etiology is unknown. We describe a 31-year-old mother, diagnosed with Coxsackievirus infection and hand-foot-and-mouth disease at 35 weeks gestation. Ultrasound at 35 weeks revealed a normal fetus and placenta. One week later, the mother experienced decreased fetal movement and ultrasound demonstrated intrauterine demise. The autopsy showed mild, acute pericarditis and hypoxic-ischemic encephalopathy. Placenta examination showed MPFD involving 80% of the parenchyma. Molecular viral analysis and serotyping showed Coxsackie A16 virus. The mother had an uneventful pregnancy 15 months later. Coxsackievirus infections in pregnant mothers are often asymptomatic. Transplacental Coxsackievirus infection is very rare but is associated with spontaneous abortion, intrauterine demise, or serious neonatal morbidity. Mild, nonspecific histologic changes have been reported in the placenta. To our knowledge, this is the first report of MPFD associated with Coxsackievirus infection. Key words: Coxsackievirus A16 infection, hand-footmouth disease, intrauterine fetal death, massive perivillous fibrin deposition
INTRODUCTION Massive perivillous fibrin deposition (MPFD), also known as gitterinfarct [1], is a rare placental disorder occurring in 0.028% to 0.5% of deliveries [2,3]. It is characterized by the accumulation of a combination of polymerized serum fibrin and trophoblast-derived extra*Corresponding author, e-mail: [email protected]
cellular matrix products, which encase chorionic villi throughout the placenta. The fibrinoid material surrounding the chorionic villi impairs transplacental gas and nutrient exchange. Maternal floor infarction (MFI) is considered a related placental disorder in which the involvement is limited to the maternal interface, and some pathologists consider these spectrums of the same process. The etiology is unclear. Massive perivillous fibrin deposition is associated with significant fetal morbidity, mortality, and recurrence. Further study is critical to elucidate its causes, to establish suitable intervention strategies to reduce the severity, and to prevent recurrence. We describe a case of a 31-year-old mother who had recent hand-foot-and-mouth disease as well as Coxsackievirus A16 infection of the placenta and MPFD, which resulted in intrauterine fetal death at 37 weeks gestation. To our knowledge, this is the first report of placental MPFD associated with Coxsackievirus infection.
CASE REPORT The mother is a 31-year-old G2, P1, T1, L1 woman. Her early pregnancy was unremarkable; obstetrical ultrasound examinations at 7 and 18 weeks, respectively, revealed a normal pregnancy with a single viable fetus. At 32 weeks gestation, the mother presented with flu-like symptoms and a sore throat. At 35 weeks, she developed a sinus infection with fever and a productive cough, followed by blisters on her oral mucous membranes, a maculopapular rash, and small blisters on the palms of her hands and the soles of her feet, and eventually extending to her chest. Her serum test for parvovirus B 19 IgM was negative but IgG was positive; cytomegalovirus (CMV) IgM was negative, and IgG was positive. Serum IgM antibody to rubella, toxoplasmosis, and syphilis were all negative. Fetal ultrasound at 35 weeks, 3 days,
Figure 1. The placenta revealed diffusely irregular strands and clumps of pale-gray induration throughout the placenta, with more than 80% of the disc volume involved. A color version of this figure is available online.
revealed a normal, single fetus in cephalic presentation with a normal fundal placenta and normal amniotic fluid. At 36 weeks, 3 days, of the pregnancy, the mother experience decreased fetal movement for 1 day, and ultrasound examination demonstrated intrauterine fetal death. A stillborn, female fetus was spontaneously delivered via vagina at 36 + 4 weeks gestational age. Consent for a complete autopsy was obtained. At autopsy, the female fetus was grossly unremarkable. The body weight (2540 g) and measurements were consistent with 35 weeks gestational age. The brain and liver weight ratio was 3.72. Microscopic examination showed a focal, mild, acute inflammatory-cell infiltrate limited to the epicardium, but no myocarditis. Blood culture results were positive for enterococcus faecalis, which was attributed to contamination at autopsy. Neuropathologic examination showed fetal hypoxic-ischemic encephalopathy with ischemic, red, neuronal changes in the dentate nucleus, superior colliculus, and pons; apoptotic bodies were present in the subiculum and pons. There was no evidence
of encephalitis. The placenta was oval shaped (17 3 16 3 2.5 cm) with a trimmed weight of 324 g (reference range, 441 g; 10th percentile, 320 g). The placenta showed macroscopically diffuse involvement with irregular strands and clumps of pale-gray induration throughout; more than 80% of the disc volume was involved (Fig. 1). Histologic examination showed diffusely transmural massive perivillous deposition of eosinophilic fibrillar and lattice-like fibrinoid material in the intervillous space (Fig. 2a). The fibrin tightly encased the villi, which showed variable stromal hypovascular/sclerotic changes and variable denudation of the surface trophoblast (Fig. 2b). Gomori trichrome stain highlighted brilliantred fibrinoid material in the intervillous space, indicating a fibrin-type fibrinoid [5], extending from the maternal surface to fetal surface and encasing 80% of the villi in all 8 random sections. There were also patchy aggregates of CD68+ histiocytes within the intervillous spaces, strongly suggestive of chronic histiocytic intervillositis (Fig. 3a,b). Placenta and umbilical cord tissue was submitted for polymerase chain reaction and reverse transcriptionpolymerase chain reaction molecular viral analysis, which was positive for enterovirus but negative for CMV, respiratory syncytial virus, parvovirus, herpes simplex, influenza, and parainfluenza viruses. Molecular serotyping by sequencing and analyzing a segment of the VP2 gene was performed, as previously described [4], and showed the enterovirus to be Coxsackie A16. Fetal lung, liver, heart, and brain submitted for virus detection were all negative. After 15 months, the mother had a subsequent, uneventful pregnancy and a live-born, healthy baby was delivered at 39 weeks gestation; the placenta was not submitted for pathology examination.
DISCUSSION Coxsackieviruses are nonenveloped viruses that have a positive single-strand RNA genome and belong to the genus Enterovirus. Coxsackie A and B viruses were initially defined by their capacity to cause flaccid or
Figure 2. (a) Diffusely massive perivillous deposition of lattice-like, fibrinoid material in the intervillous space, extending from the maternal surface to the fetal surface, encasing more than 80% of the villi. (b) Fibrinoid-encased hypovascular and sclerotic villi showing surface trophoblast damage and loss. A color version of this figure is available online.
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Figure 3. (a) Multifocal aggregates of intervillous histiocytes are strongly suggestive of chronic histiocytic intervillositis. (b) Patchy aggregates of CD68+ histiocytes are shown within the intervillous spaces. A color version of this figure is available online.
spastic paralysis, respectively, in newborn mice. In all, 23 serotypes of Coxsackie A and 6 serotypes of Coxsackie B have been described. Like all enteroviruses, most infections are asymptomatic. Different serotypes of Coxsackie A viruses have been associated with exanthemata and enanthemata (and classically with hand-foot-mouth disease) and with other diseases, such as aseptic meningitis and respiratory diseases. Different serotypes of Coxsackie B viruses are causative agents of diseases, such as myocarditis, respiratory infections, pancreatitis, and have been associated with cases of acute onset of type I diabetes [6]. Pregnant women are frequently exposed to enteroviruses. Coxsackievirus infection in pregnant women does not readily cross the placenta to cause fetal disease, but vertical transmission can occur in the perinatal period [15]. However, rare cases of transplacental passage have been documented to cause variable morbidity and mortality in fetuses and neonates. Some fetuses and newborns are not affected, despite the presence of Coxsackievirus infection in the placenta [7,8]. Two reported cases of first-trimester Coxsackie A16 placental infection were associated with spontaneous abortion at 7 and 12 weeks, respectively [7]. Intrauterine fetal demise with myocarditis, pericarditis, and meningoencephalitis in late pregnancy has been documented. Seven cases of intrauterine fetal-acquired Coxsackie infection causing severe respiratory failure and central nervous system developmental delays in newborn infants have been reported [8]. Affected live-born neonates can present with severe sepsis, hypotension, leucopenia, thrombocytopenia, and disseminated intravascular coagulopathy; severe, long-term neurologic sequelae with widespread cortical necrosis have also been described [8]. Coxsackievirus infection associated histologic changes in the placenta are not well studied. A few studies have described mild and nonspecific histologic changes, including Hofbauer cell hyperplasia, focal chronic villitis, focal hemorrhagic endovasculitis, and focal calcification [8,9]. Massive perivillous fibrin deposition and MFI are closely related disorders with considerable clinical and
pathologic overlap but unknown pathogeneses. Proposed hypotheses include maternal autoimmune disorders, cytotoxicity by pregnancy-associated major basic protein produced by abnormal X-cells, a genetic cause (because of the high recurrence rate), or a manifestation of latent herpes simplex infection [3,10,11]. Co-occurrence of MPFD and chronic histiocytic intervillositis has been reported [10]. In our current case, there was an element of this latter entity (Figure 3a). Placental fibrinoids are extracellularly deposited, histologically glossy eosinophilic materials found in every normal placenta. Immunohistochemical and ultrastructural studies have analyzed the composition of fibrinoids; 2 types of fibrinoids have been described [5,12,13]. Fibrin-type fibrinoid is derived mainly from a maternal blood product, together with other molecules and a degenerative process. Matrix-type fibrinoid is a secretory product of extravillous trophoblast cells containing laminins, collagen IV, heparin sulfate, oncofetal fibronectins, vitronectin, and glycosylated molecules. The matrix-type fibrinoid embeds the secreting cells and regulates trophoblast invasion by specific interactions with cell-surface molecules. On hematoxylin-eosin (H&E) stain, both fibrinoid types have similar eosinophilic appearance, but the matrix-type fibrinoid contains clusters of extravillous trophoblast cells, whereas fibrin-type fibrinoid is devoid of those cells [5,11]. With Gomori trichrome stain, fibrin-type fibrinoids usually stain red or orange, whereas the matrix type usually stains aniline blue or lightly green. Several studies have suggested that the deposition of fibrinoid is a secondary response to trophoblastic cell injury. The chorionic villi in our case showed the presence of a fibrin-type fibrinoid encasing the villous surfaces denuded of syncytiotrophoblast, which could suggest that Coxsackie A16 caused degenerative changes in the syncytiotrophoblast cells. We cannot rule out the possibility that the placental Coxsackie infection was coincidental to the fetal demise rather than causative, especially because the fetal tissue results were negative. However, because it is known that transplacental passage of Coxsackievirus is rare [15], in our case, perhaps, the maternal infection simply
INTRAUTERINE COXSACKIE VIRUS AND MPFD LEADS TO FETAL DEMISE
333
precipitated the fibrinoid deposition, and MPFD was the direct cause of demise. This analysis was supported by the absence of autopsy findings, except for acute ischemic changes in the brain, which were probably due to placental insufficiency caused by acute-onset MPFD. Interestingly, there was no evidence of intrauterine growth retardation (IUGR) in our case because fetal measurements, both on prenatal ultrasounds and at autopsy, were appropriate. This supports the premise that the onset of MPFD was acute and its onset was closely associated with the Coxsackie infection, as a morechronic process would likely have caused IUGR. In fact, most cases of MPFD are associated with IUGR [2,3,10]. The pathologic diagnosis of MPFD is subjective because there are no standardized criteria for the diagnosis. Deposition of perivillous fibrinoid is a normal phenomenon, occurring in every placenta, and the amount increases as pregnancy advances. Quantitative diagnostic criteria for MPFD could improve diagnostic reproducibility. Correlation of macroscopic and microscopic examination is essential in differentiating MPFD from nonspecific changes. Fox and Sebire [14] indicated that the normal placenta can withstand a loss of up to 30% of functioning villi without any evidence of adverse effects; therefore, the diagnosis of MPFD should be reserved only for those placentas in which more than 30% of villous parenchyma is obliterated by fibrin. Other authors apply the diagnosis of MPFD when more than 30% of the villi in the central region of the placenta are encased in fibrinoid material or more than 40% of the chorionic villi are involved. Weber and colleagues [10] suggested the diagnostic criteria of more than 50% of the placenta parenchyma obliterated by fibrin. The average placental area involved for the diagnosis is 50% by Bane and Gillan [3] and ranges from 20% to 90%. Several authors have emphasized that a major impediment to the diagnosis is the variability and stringency of diagnostic criteria. The extent of perivillous fibrin deposition in the placenta in our case was greater than 80%, both in gross examination and microscopic analysis, in all 8 random sections of the placenta parenchyma, which meets with the strictest diagnostic criteria for the disease. Although MPFD is known to be associated with a high risk of recurrence in subsequent pregnancies, in our case, the mother had a normal-term pregnancy with a healthy baby delivered 15 months after the onset of MPFD. The result suggests that etiology and pathogenesis of MPFD are heterogeneous. Clearly, MPFD associated with Coxsackievirus infection does not necessarily recur in a future pregnancy. In conclusion, we describe a case of placental Coxsackievirus A16 infection in a 31-year-old mother, who had recent hand-foot-mouth disease. She presented with MPFD and intrauterine fetal death at 36 weeks
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gestation. To our knowledge, this is the first report of MPFD being associated with Coxsackievirus infection. In view of the clinical course of our case, the time from initial, mild, flu-like symptoms in the mother until intrauterine fetal death was only few weeks, awareness of this possible devastating complication of Coxsackievirus infection in pregnancy should be raised among obstetricians, neonatologists, and pediatricians, thus, enabling them to make appropriate clinical decisions and provide adequate counseling to parents. Immediate induction of the labor or caesarean section should be considered. REFERENCES 1. Waters BL, Ashikaga T. Significance of perivillous fibrin/oid deposition in uterine evacuation specimens. Am J Surg Pathol 2006; 30:7602765. 2. Uxa R, Baczyk D, Kingdom JC, Viero S, Caster R, Keating S. Genetic polymorphism in fibrinolytic system of placentas with massive perivillous fibrin deposition. Placenta 2010;31: 4992505. 3. Bane AL, Gillan JE. Massive perivillous fibrinoid causing recurrent placental failure. BJOG 2003;110:2922295. 4. Pabbaraju K, Wong S, Chan EN, Tellier R. Genetic characterization of a Coxsackie A9 virus associated with aseptic meningitis in Alberta, Canada in 2010. Virol J 2013;10:93. 5. Kaufmann P, Huppertz B, Frank HG. The fibrinoids of the human placenta: origin, composition and functional relevance. Ann Anat 1996;178:4852501. 6. Pallansch M, Roos R. Enteroviruses: polioviruses, coxsackie viruses, echoviruses and newer enteroviruses. In: Fields Virology, 5th ed., Knipe DM, Howly PM, eds. Philadelphia: Lippincott Williams and Wilkins, 2007. 7. Ogilvie MM, Tearne CF. Spontaneous abortion after hand-foot-and mouth disease caused by Coxsackie virus A16. Br Med J 1980;281: 152721528. 8. Euscher E, Davis J, Holzman I, Nuovo GJ. Coxsackie virus infection of the placenta associated with neurodevelopmental delays in the newborn. Obstet Gynecol 2001;98:101921026. 9. Batcup G, Holt P, Hambling MH, Gerlis LM, Glass MR. Placental and fetal pathology in Coxsackie virus A9 infection: a case report. Histopathology 1985;9:122721235. 10. Weber MA, Nikkels PG, Hamoen K, Duvekot JJ, de Krijer RR. Co-occurrence of massive perivillous fibrin deposition and chronic intervillositis: case report. Pediatr Dev Pathol 2006;9: 2342238. 11. Benirschke K, Kaufmann P, Baergen RN. Pathology of the Human Placenta, 5th ed. New York: Springer, 2006. 12. Frank HG, Malekzadeh F, Kertschanska S, Crescimanno C, Castellucci M, Lang I, et al. Immunohistochemistry of two different types of placental fibrinoid. Acta Anat (Basel) 1994;150:55268. 13. Vernof KK, Benirschke K, Kephart GM, Wasmoen TL, Gleich GJ. Maternal floor infarction: relationship to X cells, major basic protein, and adverse perinatal outcome. Am J Obstet Gynecol 1992; 167:135521363. 14. Fox H, Sebire NJ. Pathology of the Placenta, Major Problems in Pathology, 3rd ed. Philadelphia: Saunders Elsevier, 2007. 15. Amstey MS, Miller RK, Munegus MA, di Sant’Agnese PA. Enterovirus in pregnant women and the perfused placenta. Am J Obstet Gynecol 1988;158:775.
