Caracterização da infecção placentária pelo vírus zika em humanos: Uma revisão da literatura

Venceslau, Emanuella Meneses; Guida, José Paulo; Amaral, Eliana; Modena, José Luis Proença; Costa, Maria Laura

doi:10.1055/s-0040-1712126

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Brasil

Revista Brasileira de Ginecologia e Obstetrícia

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Brasil

Español English

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Sumário

Review Article • Rev. Bras. Ginecol. Obstet. 42 (09) • Set 2020 • https://doi.org/10.1055/s-0040-1712126 copiar

Caracterização da infecção placentária pelo vírus zika em humanos: Uma revisão da literatura

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Objetivo

O objetivo desta revisão é apresentar uma avaliação sistemática dos achados relacionados à infecção por zika vírus (ZIKV) na placenta humana.

Fontes de dados

As bases de dados EMBASE, PUBMED, e SCIELO foram pesquisadas, até junho de 2019, sem qualquer restrição de língua.

Seleção dos estudos

Os termos placenta E zika virus foram utilizados na busca. Foram incluídos estudos que reportassem achados placentários de infecção em seres humanos, enquanto estudos experimentais, revisões, notas e editoriais foram excluídos. Um total de 436 estudos foram identificados, e 243 tiveram seus títulos lidos após a exclusão de duplicatas. Cento e vinte e oito artigos tiveram seus resumos avaliados, dos quais 32 foram incluídos na análise final (18 relatos de caso, 10 séries de casos, e 4 estudos de coorte).

Dados obtidos

Foram pesquisados dados relativos ao autor, ano da publicação, desenho do estudo, número de participantes, número de amostras de placenta, início dos sintomas, desfechos perinatais, e principais achados histológicos. Síntese dos dados Os principais achados placentários descritos foram leves e inespecíficos, similares a outras infecções placentárias, incluindo infecção placentária crônica, vilosite crônica, aumento das células de Hofbauer, depósitos irregulares de fibrina, aumento das células mononucleares no estroma viloso, imaturidade vilosa, edema, hipervascularização, fibrose estromal, calcificação, e necrose focal dos sincicitrofoblastos.

Conclusão

Infecções por ZIKV têm achados placentários inespecíficos, similares aos de outras infecções do grupo toxoplasmose, rubéola, citomegalovírus e herpes (TORCH). Caracterizar e padronizar os achados placentários após infecção por ZIKV é fundamental para entender o mecanismo das infecções congênitas.

Palavras-chave:
Zika vírus; ZIKV; placenta; células de Hofbauer; TORCH

Author, year	Type of study	Participants/placentas sampled	Onset of symptoms (trimester)				Perinatal outcomes				Main findings on placental evaluation and overall findings
Author, year	Type of study	Participants/placentas sampled	1^st	2^nd	3^rd	N/A	A	B	C	D	Main findings on placental evaluation and overall findings
Driggers et al (2016)¹⁴14 Driggers RW, Ho CY, Korhonen EM, Kuivanen S, Jääskeläinen AJ, Smura T, et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med. 2016;374 (22):2142-2151. Doi: 10.1056/NEJMoa1601824 https://doi.org/10.1056/NEJMoa1601824...	Case report	1/1	1	–	–	–	–	–	1	–	High viral load found in placenta, fetal membranes and umbilical cord by RT-PCR.ZIKV RNA in Amniotic fluid, fetal brain, liver, lung and spleen.
Martines et al (2016)¹¹11 Martines RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J, et al. Notes from the field: evidence of zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses-Brazil, 2015.MMWR Morb Mortal Wkly Rep. 2016;65(06):159-160. Doi: 10.15585/ mmwr.mm6506e1 https://doi.org/10.15585/...	Case report	4 / 4	2	–	2	–	2	–	–	2	Placenta with fibrosis, calcification, and deposits of fibrin. Material consistent with third trimester gestation = RT-PCR negative.Two abortions, one had dense and heterogeneous chorionic villitis with calcification, sclerosis, edema, increased perivillous fibrin deposition, and patchy lympho histiocytic intervillositis and the other had minute fragments of placental. Both placental RT-PCR positive for ZIKV.
Martines et al (2016)¹²12 Martines RB, Bhatnagar J, de Oliveira Ramos AM, Davi HP, Iglezias SP, Kanamura CT, et al. Pathology of congenital Zika syndrome in Brazil: a case series. Lancet. 2016;388(10047):898-904. Doi: 10.1016/S0140-6736(16)30883-2 https://doi.org/10.1016/S0140-6736(16)30...	Case series	5/2	1	–	–	4	2	–	2	1	RT-PCR ZIKV positive in all samples.IHC: ZIKV antigens in chorionic villi of a first trimester placenta.
Melo et al (2016)¹⁵15 Melo ASO, Aguiar RS, Amorim MM, Arruda MB, Melo FO, Ribeiro ST, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016;73(12):1407-1416. Doi: 10.1001/jamaneurol.2016.3720 https://doi.org/10.1001/jamaneurol.2016....	Case series	11/11	9	1	–	1	–	–	3	8	PCR ZIKV performed in nine placentas, two positives.
Mlakar et al (2016)¹⁶16 Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika virus associatedwith microcephaly. N Engl J Med. 2016; 374(10):951-958. Doi: 10.1056/NEJMoa1600651 https://doi.org/10.1056/NEJMoa1600651...	Case report	1/1	1	–	–	–	–	1	–	–	Ultrasound scan performed at 29 weeks showed microcephaly with brain and placental calcification.RT-PCR ZIKV positive in fetal brain tissue
Noronha et al (2016)¹³13 Noronha Ld, Zanluca C, AzevedoML, Luz KG, Santos CN. Zika virus damages the human placental barrier and presents marked fetal neurotropism. Mem Inst Oswaldo Cruz. 2016;111(05):287-293. Doi: 10.1590/0074-02760160085 https://doi.org/10.1590/0074-02760160085...	Case report	5/3	3	–	1	1	1	–	–	4	RT-PCR ZIKV positive in all samples. Main pathological findings: chronic placentitis, hyperplasia in villous HCs.IHC with the 4G2 anti-flavivirus monoclonal antibody analysis showed: immunopositivity in HCs and some histiocytes in intervillous spaces, diffusely distributed immunopositivity in some glial cells.
Sarno et al (2016)¹⁷17 Sarno M, Sacramento GA, Khouri R, doRosárioMS, Costa F, Archanjo G, et al. Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise. PLoS Negl Trop Dis. 2016;10 (02):e0004517. Doi: 10.1371/journal.pntd.0004517 https://doi.org/10.1371/journal.pntd.000...	Case report	1/1	–	–	–	–	–	–	1	–	RT-PCR ZIKV negative in placental sample.
van der Eijk et al (2016)¹⁸18 van der Eijk AA, van Genderen PJ, Verdijk RM, Reusken CB, Mögling R, van Kampen JJ, et al. Miscarriage associated with Zika virus infection. N Engl J Med. 2016;375(10):1002-1004. Doi: 10.1056/NEJMc1605898 https://doi.org/10.1056/NEJMc1605898...	Case report	1/1	1	–	–	–	1	–	–	–	Placental histopathological and IHC investigation: no inflammation markers.RT-PCR ZIKV positive in the amniotic fluid, fetal and placental tissue.In situ hybridization (ISH) only found ZIKV in amniotic epithelium.
Acosta-Reyes et al (2017)¹⁹19 Acosta-Reyes J, Navarro E, Herrera MJ, Goenaga E, Ospina ML, Parra E, et al. Severe neurologic disorders in 2 fetuses with Zika virus infection, Colombia. Emerg Infect Dis. 2017;23(06): 982-984. Doi: 10.3201/eid2306.161702 https://doi.org/10.3201/eid2306.161702...	Case report	2/2	1	1	–	–	1	–	–	–	Placental ZIKV RT-PCR positive in one case.Histological analysis: increase in perivillous fibrin deposit, chronic lymphocytic deciduitis in both cases.
Bhatnagar et al (2017)²⁰20 Bhatnagar J, Rabeneck DB, Martines RB, Reagan-Steiner S, Yokabed E, Estetter LBC, et al. Zika virus RNA replication and persistence in brain and placental tissue. Emerg Infect Dis. 2017; 23(03):405-414. Doi: 10.3201/eid2303.161499 https://doi.org/10.3201/eid2303.161499...	Case series	44/44^H	19	24	–	1	11	3	3	27	ZIKV RT-PCR positive in 32 placental samples.ISH positive in 16 of the cases positives by RT-PCR.
Chen et al (2017)²¹21 Chen L, Hafeez F, Curry CL, Elgart G. Cutaneous eruption in a U.S. woman with locally acquired Zika virus infection. N Engl J Med. 2017;376(04):400-401. Doi: 10.1056/NEJMc1610614 https://doi.org/10.1056/NEJMc1610614...	Case report	1/1	–	1	–	–	–	–	–	1	RT-PCR ZIKV negative in placental sample.
Mattar et al (2017)²²22 Mattar S, Ojeda C, Arboleda J, Arrieta G, Bosch I, Botia I, et al. Case report: microcephaly associated with Zika virus infection, Colombia. BMC Infect Dis. 2017;17(01):423. Doi: 10.1186/ s12879-017-2522-6 https://doi.org/10.1186/...	Case report	1/1	–	1	–	–	–	–	–	1	RT-PCR ZIKV positive in placental sample.ZIKV not found in umbilical cord or serum.
Rabelo et al (2017)²³23 Rabelo K, de Souza Campos Fernandes RC, de Souza LJ, Louvain de Souza T, Dos Santos FB, Guerra Nunes PC, et al. Placental histopathologyand clinicalpresentationof severe congenitalZika syndrome in a human immunodeficiency virus-exposed uninfected infant. Front Immunol. 2017;8:1704. Doi: 10.3389/fimmu.2017.01704 https://doi.org/10.3389/fimmu.2017.01704...	Case report	1/1	–	–	–	1	–	–	–	1	IHC revealed presence of ZIKV antigens.Severe damage to maternal decidua and chorionic villitis, with large areas of fibrinoid necrosis and perivascular inflammatory infiltrates. Dense and heterogenous calcification observed.
Reagan-Steiner et al (2017)²⁴24 Reagan-Steiner S, Simeone R, Simon E, Bhatnagar J, Oduyebo T, Free R, et al; U.S. Zika Pregnancy Registry Collaboration; Zika Virus Response Epidemiology and Surveillance Task Force Pathology Team. Evaluation of placental and fetal tissue specimens for Zika virus infection - 50 states and district of Columbia, January- December, 2016. MMWR Morb Mortal Wkly Rep. 2017;66(24): 636-643. Doi: 10.15585/mmwr.mm6624a3 https://doi.org/10.15585/mmwr.mm6624a3...	Case series	627/627	131	153	–	343	81	–	–	546	Of 546, 60 placental sample RT-PCR ZIKV positives.In 81 samples of pregnancy losses, 18 placental sample RT-PCR ZIKV positives.IHC performed in 91 placentas from livebirths and 7 had evidences of ZIKV infection.
Ritter et al (2017)¹⁰10 Ritter JM, Martines RB, Zaki SR. Zika virus: pathology from the pandemic. Arch Pathol Lab Med. 2017;141(01):49-59. Doi: 10.5858/arpa.2016-0397-SA https://doi.org/10.5858/arpa.2016-0397-S...	Case report^E	4/2	2	–	–	2	1	–	1	–^F	One sample, histological analysis showed: patchy villous hypercellularity, focal perivillous fibrin deposition, increased HCs and focal calcification.
Rosenberg et al (2017)⁹9 Rosenberg AZ, Yu W, Hill DA, Reyes CA, Schwartz DA. Placental pathology of Zika virus: viral infection of the placenta induces villous stromal macrophage (Hofbauer Cell) proliferation and hyperplasia. Arch Pathol Lab Med. 2017;141(01):43-48. Doi: 10.5858/arpa.2016-0401-OA https://doi.org/10.5858/arpa.2016-0401-O...	Case report	1/1	1	–	–	–	–	1	–	–	RT-PCR ZIKV positive in the placenta and fetal brain.Placenta demonstrated focally stromal edema, hydropic chorionic villi with hyperplasia and focal proliferation of HCs. prominent hypercellularity of the villous stroma.IHC with inflammatory markers (CD163 and CD8) found in HCs.ISH positive for ZIKV demonstrated scattered, strongly positive staining cells within the villous stroma of the chorionic villi, which were presumably HCs.
Schaub et al (2017)²⁵25 Schaub B, Vouga M, Najioullah F, Gueneret M, Monthieux A, Harte C, et al. Analysis of blood from Zika virus-infected fetuses: a prospective case series. Lancet Infect Dis. 2017;17(05):520-527. Doi: 10.1016/S1473-3099(17)30102-0 https://doi.org/10.1016/S1473-3099(17)30...	Case series	8/8	6^I	–	–	–	3	–	–	1^F	RT-PCR ZIKV positive in three samples.
Schwartz (2017)²⁶26 Schwartz DA. Viral infection, proliferation, and hyperplasia of Hofbauer cells and absence of inflammation characterize the placental pathology of fetuses with congenital Zika virus infection. Arch Gynecol Obstet. 2017;295(06):1361-1368. Doi: 10.1007/s00404-017-4361-5 https://doi.org/10.1007/s00404-017-4361-...	Case series	12/12	–	–	–	12	–	–	–	12	Placentas from fetuses with congenital ZIKV infection didn't present placental inflammation.IHC: special stains reveal proliferation and prominent hyperplasia of HCs, in the chorionic villi of infected placentas. ZIKV infection present in HCs from second and third trimester placentas.
Noronha et al (2018)²⁷27 de Noronha L, Zanluca C, Burger M, Suzukawa AA, Azevedo M, Rebutini PZ, et al. Zika virus infection at different pregnancy stages: anatomopathological findings, target cells and viral persistence in placental tissues. Front Microbiol. 2018;9:2266. Doi: 10.3389/fmicb.2018.02266 https://doi.org/10.3389/fmicb.2018.02266...	Case series	24/24	5	8	6	5	1	–	–	23	Villous immaturity was the main histological finding.IHC: Hyperplasia of HCs observed in the third trimester in placental tissues. HCs were the only ZIKV-positive fetal cells found in placentas that persisted until birth.33% of women infected during pregnancy gave birth to babies with congenital anomalies.No pattern correlating the gestational stage in the infection, the positivity of HCs in the placenta due to IHC and the presence of congenital malformations at birth.
Esquivel et al (2018)²⁸28 EsquivelM, Avaad-Portari E, Vasconcelos ZC, Moreira ME, Gaw SL. Vertical transmission and placental pathology of twin pregnancies from Zika virus infectedmothers. Am J Obstet Gynecol. 2018; 218(1, Suppl)520. Doi: 10.1016/j.ajog.2017.11.410 https://doi.org/10.1016/j.ajog.2017.11.4...	Cohort	3/6	1	2	1	–	–	–	–	3	Patient 1: Placental PCR negative, but both twins were PCR-positive.Patient 2: Both placentas and twins were PCR-positive at birth.Patient 3: One twin and associated placenta PCR-positive, the second twin and placenta PCR-negative.All six placentas with villous immaturity and other placental histopathologic findings distinct in each placental pair.These results suggest that each twin should be evaluated individually for Zika infection as ZIKV may not transmit equally to each fetus.
Maykin et al (2018)²⁹29 Maykin M, Avaad-Portari E, Esquivel M, Pereira JP Jr., Fisher SJ, Moreira ME, et al. Placental histopathologic findings in Zikainfected pregnancies. Am J Obstet Gynecol. 2018;218(1, Suppl) 520-521. Doi: 10.1016/j.ajog.2017.11.411 https://doi.org/10.1016/j.ajog.2017.11.4...	Cohort	29/29	2	22	1	4	–	–	–	29	PCR ZIKV positive in 25 placentas.Ten placental pathological findings: delayed villous maturation, chronic deciduitis, stromal fibrosis and HC hyperplasia.
Mletzko e Schildgen (2018)³⁰30 Mletzko J, Schildgen O. Absence of Zika virus in abort and placental tissue in a German cohort. Rev Med Microbiol. 2018; 29(01):17-19. Doi: 10.1097/MRM.0000000000000121 https://doi.org/10.1097/MRM.000000000000...	Cohort	301/121	–	–	–	300	180	–	–	121	RT-PCR ZIKV negative in all placentas and tissues from spontaneous abortions.
Rabelo et al (2018)³¹31 Rabelo K, Souza LJ, Salomão NG, Oliveira ERA, Sentinelli LP, Lacerda MS, et al. Placental inflammation and fetal injury in a rare Zika case associated with Guillain-Barré syndrome and abortion. Front Microbiol. 2018;9:1018. Doi: 10.3389/fmicb.2018.01018 https://doi.org/10.3389/fmicb.2018.01018...	Case report	1/1	1	–	–	–	1	–	–	–	Histological analyses of the placenta and fetal organs revealed different types of tissue abnormalities: inflammation, hemorrhage, edema and necrosis in placenta, as well as tissue disorganization in the fetus.IHC: Increased cellularity (HCs and TCD8+ lymphocytes), expression of local pro-inflammatory cytokines such as IFN-γ and TNF-α, and other markers, such as RANTES/CCL5 and VEGFR2, supported placental inflammation and dysfunction.
Sassetti et al (2018)³²32 Sassetti M, Zé-Zé L, Franco J, Cunha JD, Gomes A, Tomé A, Alves MJ. First case of confirmed congenital Zika syndrome in continental Africa. Trans R Soc Trop Med Hyg. 2018;112(10):458-462. Doi: 10.1093/trstmh/try074 https://doi.org/10.1093/trstmh/try074...	Case report	1/1	1	–	–	–	–	–	–	1	RT-PCR ZIKV negative in Placenta and blood.RT-PCR positive in the newborn urine sample collected on day 1 after birth.
Turley et al (2018)³³33 Turley M, Valentine G, Seferovic M, Rac M, Eppes C, Major A, et al. Importance of placental testing in congenital zika virus (zikv) infection and fetal malformation syndrome. Am J Obstet Gynecol. 2018;218(1, Suppl)54-55. Doi: 10.1016/j.ajog.2017.10.484 https://doi.org/10.1016/j.ajog.2017.10.4...	Case series	4/4	–	–	–	4	–	–	–	4	All 4 cases demonstrated positive placental testing by multiple modalities.IHC: tissues were stained against E glycoprotein of the ZIKV envelope with 4G2 monoclonal antibody revealing strong but localized signal in the chorionic villus parenchyma and villous lumen.PCR amplicons of the ZIKV genome were amplified by RT-PCR from placenta in all cases. Bioanalyzer assessment of RT-PCR product confirmed the highest amounts of ZIKV in placenta and verified amplicon size.
Wongsurawat et al (2018)³⁴34 Wongsurawat T, Jenjaroenpun P, Athipanyasilp N, Kaewnapan B, Leelahakorn N, Angkasekwinai N, et al. Genome sequences of Zika virus strains recoveredfromamnioticfluid, placenta, and fetal brain of a microcephaly patient in Thailand, 2017. Microbiol Resour Announc. 2018;7(11):e01020-e18. Doi: 10.1128/MRA.01020-18 https://doi.org/10.1128/MRA.01020-18...	Case report	1/1	1	–	–	–	1	–	–	–	PCR ZIKV positive in the placenta and brain.
Felix et al (2017)³⁵35 Felix A, Hallet E, Favre A, Kom-Tchameni R, Defo A, Fléchelles O, et al. Cerebral injuries associated with Zika virus in utero exposure in children without birth defects in French Guiana: Case report. Medicine (Baltimore). 2017;96(51):e9178. Doi: 10.1097/MD.0000000000009178 https://doi.org/10.1097/MD.0000000000009...	Case report	2/2	2	–	–	–	–	–	–	2	PCR ZIKV negative in placenta fragments, blood and urine.ZIKV serology performed only showed presence of IgG antibodies of maternal origin.
Merriam et al (2019)³⁶36 Merriam AA, Nhan-Chang CL, Huerta-Bogdan BI, Wapner R, Gyamfi-Bannerman C. A single-center experiencewith a pregnant immigrant population and Zika virus serologic screening in New York City. Am J Perinatol. 2019; [Epub ahead of print] . Doi: 10.1055/s-0039-1688819 https://doi.org/10.1055/s-0039-1688819...	Cohort	70/70	–	–	–	70	–	4	–	63	PCR positive in 1 placenta.PCR positive in urine and serum in five and nine women respectively, and two women had both positive urine and serum PCR.
Rodó et al (2019)³⁷37 Rodó C, Suy A, Sulleiro E, Soriano-Arandes A, Maiz N, García-Ruiz A, et al. Pregnancy outcomes after maternal Zika virus infection in a non-endemic region: prospective cohort study. Clin Microbiol Infect. 2019;25(05):633.e5-633.e9. Doi: 10.1016/j.cmi.2019.02.008 https://doi.org/10.1016/j.cmi.2019.02.00...	Case series	72/72	16	41	14	–	–	–	–	–	RT-PCR ZIKV positive for 10 placentas.Sorological assay positive for the other 62 women.2 cases of central nervous system anomalies and 1 miscarriage, all in women with first trimester infection.
Santos et al (2020)³⁸38 Santos GR, Pinto CAL, Prudente RCS, Bevilacqua EMAF, Witkin SS, Passos SD; Zika Virus Cohort Study Group. Case report: histopathologic changes in placental tissue associated with vertical transmission of Zika virus. Int J Gynecol Pathol. 2020;39(02): 157-162. Doi: 10.1097/PGP.0000000000000586 https://doi.org/10.1097/PGP.000000000000...	Case report	1/1	1	–	–	–	–	–	–	1	Deciduitis present on maternal surface of the placenta, with a prevalence of lymphocytes associated with vasculitis.IHC: HCs found in placental tissue, specific-ZIKV protein found in placental cells.IHC with high level of CD3 T lymphocytes present in addition to CD4 and CD8 cells. High expression of the apoptosis inhibitor, Bcl-2, observed in the syncytiotrophoblasts.
Seferovic et al (2019)³⁹39 Seferovic MD, Turley M, Valentine GC, Rac M, Castro ECC, Major AM, et al. Clinical importance of placental testing among suspected cases of congenital Zika syndrome. Int J Mol Sci. 2019;20 (03):E712. Doi: 10.3390/ijms20030712 https://doi.org/10.3390/ijms20030712...	Case series	4/4	2	2	–	–	–	–	–	4	RT-PCR ZIKV performed on placenta, membrane and cord samples.ZIKV was detected in all placental specimens in cases 1, 2 and 3 (affected by CZS), but not by case 4 (unaffected).ZIKV detected in the membranes and cord of cases 2 and 3, but not in cases 1 and 4.Histological and IHC examination of placentas reveals evidence of ZIKV infection and active in cases 1, 2 and 3.ISH positive in cases 1, 2 and 3.
Yarrington et al (2019)⁴⁰40 Yarrington CD, Hamer DH, Kuohung W, Lee-Parritz A. Congenital Zika syndrome arising fromsexual transmission of Zika virus, a case report. Fertil Res Pract. 2019;5:1.Doi: 10.1186/s40738-018-0053-5 https://doi.org/10.1186/s40738-018-0053-...	Case report	1/1	–	–	–	–	–	–	–	1	RT-PCR ZIKV positive in placental sample.Evaluation for other causes of microcephaly negative.

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[1] Address for correspondence Jose Paulo Guida, MD, MsC, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil (e-mail: zepauloguida@gmail.com).