Yonsei Med J.  2014 Nov;55(6):1562-1567. 10.3349/ymj.2014.55.6.1562.

Coxsackievirus B Infection Is Highly Related with Missed Abortion in Korea

• Hwang JH
• Kim JW
• Hwang JY
• Lee KM
• Shim HM
• Bae YK
• Paik SS
• Park H

• KMID: 2070203
• DOI: http://doi.org/10.3349/ymj.2014.55.6.1562

Abstract

PURPOSE
This study investigated the possible relationship between viral infection and first trimester pregnancy loss.
MATERIALS AND METHODS
A prospective study was performed on 51 gravidas with missed abortion, fetal anomaly, pre-term delivery, and full-tem delivery at Hanyang University Hospital. Enteroviruses were detected by semi-nested reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry in abortive tissues and placentas. Enterovirus serotypes were confirmed by genome sequencing. Herpesviruses were detected by PCR.
RESULTS
Coxsackievirus B3 (CVB3) was detected in 8 of 14 missed abortion cases, 1 of 27 full-term cases, and none of the 9 pre-term cases. Coxsackievirus B1 (CVB1) was detected in an encephalocele case. Herpes simplex virus type 1 was found in 4 full-term cases, 3 pre-term cases, and none of the missed abortion cases.
CONCLUSION
The prevalence of CVB3 was significantly higher in missed abortion cases compared to full-term or pre-term delivery cases. CVB infection may therefore be an important etiological agent of missed abortion.

Keyword

Coxsackievirus; missed abortion; fetal anomaly

MeSH Terms

Abortion, Missed/*etiology
Adult
Coxsackievirus Infections/complications/*diagnosis/virology
Enterovirus B, Human/genetics/*isolation & purification
Female
Humans
Immunohistochemistry
Placenta/virology
Pregnancy
Pregnancy Complications, Infectious/*virology
Pregnancy Trimester, First
Prevalence
Prospective Studies
Republic of Korea
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA
Uterus/*virology

Figure

• 

  Fig. 1 Ultrasound examination of a malformation case revealed a single female fetus with an irregular, predominantly cystic, heterogeneous mass. The mass, measuring 2.0×1.3 cm, protruded externally from the occiput, disfiguring the head of the fetus.

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  Fig. 2 Immunohistochemistry for CVB3 in tissues using anti-CVB3 monoclonal antibody. The cytoplasms of endometrial glandular epithelial cells are strongly stained in the three CVB3 positive missed abortive tissues with brown color (A, B, and C). There are no specific staining in CVB3 negative missed abortive tissue (D), full-term (E), and pre-term (F) placentas. CVB3, Coxsackievirus B3.

• 

  Fig. 3 The immunohistochemical analysis of the enteroviral VP1 capsid protein from tissues in an encephalocele case. VP1 was highly expressed in the epithelium and muscle layer of the tongue (A) and respiratory epithelium (B), mucosal and muscle layer of the small intestine (C), and leg muscles (D).

Reference

1. Sauerbrei A, Glück B, Jung K, Bittrich H, Wutzler P. Congenital skin lesions caused by intrauterine infection with coxsackievirus B3. Infection. 2000; 28:326–328.

2. Euscher E, Davis J, Holzman I, Nuovo GJ. Coxsackie virus infection of the placenta associated with neurodevelopmental delays in the newborn. Obstet Gynecol. 2001; 98:1019–1026.

3. Bendig JW, Franklin OM, Hebden AK, Backhouse PJ, Clewley JP, Goldman AP, et al. Coxsackievirus B3 sequences in the blood of a neonate with congenital myocarditis, plus serological evidence of maternal infection. J Med Virol. 2003; 70:606–609.

4. Genen L, Nuovo GJ, Krilov L, Davis JM. Correlation of in situ detection of infectious agents in the placenta with neonatal outcome. J Pediatr. 2004; 144:316–320.

5. Cheng LL, Ng PC, Chan PK, Wong HL, Cheng FW, Tang JW. Probable intrafamilial transmission of coxsackievirus b3 with vertical transmission, severe early-onset neonatal hepatitis, and prolonged viral RNA shedding. Pediatrics. 2006; 118:e929–e933.

6. Ornoy A, Tenenbaum A. Pregnancy outcome following infections by coxsackie, echo, measles, mumps, hepatitis, polio and encephalitis viruses. Reprod Toxicol. 2006; 21:446–457.

7. Konstantinidou A, Anninos H, Spanakis N, Kotsiakis X, Syridou G, Tsakris A, et al. Transplacental infection of Coxsackievirus B3 pathological findings in the fetus. J Med Virol. 2007; 79:754–757.

8. Frisk G, Diderholm H. Increased frequency of coxsackie B virus IgM in women with spontaneous abortion. J Infect. 1992; 24:141–145.

9. Axelsson C, Bondestam K, Frisk G, Bergström S, Diderholm H. Coxsackie B virus infections in women with miscarriage. J Med Virol. 1993; 39:282–285.

10. Brown S. Miscarriage and its associations. Semin Reprod Med. 2008; 26:391–400.

11. Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988; 319:189–194.

12. Seok SH, Kang SH, Lee SJ, Hwang TY, Bae YK. Reduced expression of claudin-7 correlates with invasiveness and nuclear grade of breast carcinomas. Korean J Pathol. 2007; 41:158–164.

13. Basso NG, Fonseca ME, Garcia AG, Zuardi JA, Silva MR, Outani H. Enterovirus isolation from foetal and placental tissues. Acta Virol. 1990; 34:49–57.

14. Hwang JY, Lee KM, Kim YH, Shim HM, Bae YK, Hwang JH, et al. Pregnancy loss following coxsackievirus b3 infection in mice during early gestation due to high expression of coxsackievirus-adenovirus receptor (CAR) in uterus and embryo. Exp Anim. 2014; 63:63–72.

15. Asher DR, Cerny AM, Weiler SR, Horner JW, Keeler ML, Neptune MA, et al. Coxsackievirus and adenovirus receptor is essential for cardiomyocyte development. Genesis. 2005; 42:77–85.

16. Dorner AA, Wegmann F, Butz S, Wolburg-Buchholz K, Wolburg H, Mack A, et al. Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development. J Cell Sci. 2005; 118(Pt 15):3509–3521.

17. Honda T, Saitoh H, Masuko M, Katagiri-Abe T, Tominaga K, Kozakai I, et al. The coxsackievirus-adenovirus receptor protein as a cell adhesion molecule in the developing mouse brain. Brain Res Mol Brain Res. 2000; 77:19–28.

18. Kamei S, Hersch SM, Kurata T, Takei Y. Coxsackie B antigen in the central nervous system of a patient with fatal acute encephalitis: immunohistochemical studies of formalin-fixed paraffin-embedded tissue. Acta Neuropathol. 1990; 80:216–221.

19. Chung SK, Kim JY, Kim IB, Park SI, Paek KH, Nam JH. Internalization and trafficking mechanisms of coxsackievirus B3 in HeLa cells. Virology. 2005; 333:31–40.

20. Watson WJ, Awadallah S, Jaqua MJ. Intrauterine infection with coxsackievirus: is it a cause of congenital cardiac malformations? Infect Dis Obstet Gynecol. 1995; 3:79–81.

21. Kim H, Kang B, Hwang S, Hong J, Chung J, Kim S, et al. Molecular characteristics of human coxsackievirus B1 infection in Korea, 2008-2009. J Med Virol. 2013; 85:110–115.

22. Avgil M, Ornoy A. Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection. Reprod Toxicol. 2006; 21:436–445.

23. Kapranos NC, Kotronias DC. Detection of herpes simplex virus in first trimester pregnancy loss using molecular techniques. In Vivo. 2009; 23:839–842.

24. Gervasi MT, Romero R, Bracalente G, Chaiworapongsa T, Erez O, Dong Z, et al. Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy. J Matern Fetal Neonatal Med. 2012; 25:2002–2013.

25. Silasi M. Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy. Am J Reprod Immunol. 2013; 69:195–196.

26. Garceau R, Leblanc D, Thibault L, Girouard G, Mallet M. Herpes simplex virus type 1 is the leading cause of genital herpes in New Brunswick. Can J Infect Dis Med Microbiol. 2012; 23:15–18.