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Published in: BMC Pregnancy and Childbirth 1/2019

Open Access 01-12-2019 | Polymerase Chain Reaction | Research article

Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection

Authors: Yuka Torii, Shigeru Yoshida, Yoichiro Yanase, Takashi Mitsui, Kazuhiro Horiba, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-ichi Kawada, Tomomi Kotani, Mamoru Yamashita, Yoshinori Ito

Published in: BMC Pregnancy and Childbirth | Issue 1/2019

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Abstract

Background

Cytomegalovirus (CMV) is one of the most frequent pathogens for congenital infections. Most cases of congenital CMV infection (cCMV) are asymptomatic at birth, but sensorineural hearing loss (SNHL) or neurodevelopmental delay can appear later in childhood. This prospective study examined the practicability of serological screening for anti-CMV immunoglobulin (Ig) G and anti-CMV IgM in pregnant women.

Methods

A total of 11,753 pregnant women were examined for CMV IgG and CMV IgM during the first or second trimester. When IgM was positive, IgG was reevaluated more than two weeks later. When IgG was negative, IgG was reevaluated in the second or third trimester. All neonates from mothers with positive/borderline IgM or IgG seroconversion underwent polymerase chain reaction assay for CMV using urine samples to diagnose cCMV. Levels of IgG and IgM were compared between mothers with and without cCMV. Receiver operating characteristic (ROC) curves for IgM titers were analyzed.

Results

Eight of 500 neonates (1.6%) born from mothers with positive IgG and positive IgM, and 3 of 13 neonates (23.1%) born from mothers with IgG seroconversion were diagnosed with cCMV. Neither IgM titers nor IgG titers differed significantly between cCMV and non-cCMV groups. The area under the ROC curve was 0.716 and the optimal cut-off for IgM was 7.28 index (sensitivity = 0.625, specificity = 0.965, positive predictive value = 0.238, negative predictive value = 0.993). Titers of IgG were not frequently elevated in pregnant women with positive IgM during the observation period, including in those with cCMV. All 11 cCMV cases were asymptomatic at birth and none had shown SNHL or developmental delay as of the last regular visit (mean age, 40 months).

Conclusions

Seroconversion of CMV IgG and high-titer IgM during early pregnancy are predictors of cCMV. High IgM titer (> 7.28 index) is a predictor despite relatively low sensitivity. Levels of IgG had already plateaued at first evaluation in mothers with cCMV. Maternal screening offered insufficient positive predictive value for diagnosing cCMV, but allowed identifying asymptomatic cCMV cases in an early stage.
Literature
1.
go back to reference Koyano S, Inoue N, Oka A, Moriuchi H, Asano K, Ito Y, Yamada H, Yoshikawa T, Suzutani T. Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study. BMJ Open. 2011;1(1):e000118.CrossRef Koyano S, Inoue N, Oka A, Moriuchi H, Asano K, Ito Y, Yamada H, Yoshikawa T, Suzutani T. Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study. BMJ Open. 2011;1(1):e000118.CrossRef
2.
go back to reference Numazaki K, Fujkawa T. Prevalence of serum antibodies to cytomegalovirus in pregnant women in Sapporo, Japan. Int J Infect Dis. 2002;6(2):147–8.CrossRef Numazaki K, Fujkawa T. Prevalence of serum antibodies to cytomegalovirus in pregnant women in Sapporo, Japan. Int J Infect Dis. 2002;6(2):147–8.CrossRef
3.
go back to reference Lim Y, Lyall H. Congenital cytomegalovirus - who, when, what-with and why to treat? J Inf Secur. 2017;74(Suppl 1):S89–94. Lim Y, Lyall H. Congenital cytomegalovirus - who, when, what-with and why to treat? J Inf Secur. 2017;74(Suppl 1):S89–94.
4.
go back to reference Pass RF: Cytomegalovirus. In: Pediatric Infectious Diseases. 4th edn. Edited by Sarah S. Long LKP, Charles G. Prober Elsevier; 2012: 1044–1051. Pass RF: Cytomegalovirus. In: Pediatric Infectious Diseases. 4th edn. Edited by Sarah S. Long LKP, Charles G. Prober Elsevier; 2012: 1044–1051.
5.
go back to reference Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013;26(1):86–102.CrossRef Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013;26(1):86–102.CrossRef
6.
go back to reference Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG, Sanchez PJ, Bernstein DI, Tolan RW Jr, Novak Z, et al. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med. 2011;364(22):2111–8.CrossRef Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG, Sanchez PJ, Bernstein DI, Tolan RW Jr, Novak Z, et al. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med. 2011;364(22):2111–8.CrossRef
7.
go back to reference Ross SA, Ahmed A, Palmer AL, Michaels MG, Sanchez PJ, Bernstein DI, Tolan RW Jr, Novak Z, Chowdhury N, Fowler KB, et al. Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens. J Infect Dis. 2014;210(9):1415–8.CrossRef Ross SA, Ahmed A, Palmer AL, Michaels MG, Sanchez PJ, Bernstein DI, Tolan RW Jr, Novak Z, Chowdhury N, Fowler KB, et al. Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens. J Infect Dis. 2014;210(9):1415–8.CrossRef
8.
go back to reference Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, Vaudry W, Pass RF, Kiell JM, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16–25.CrossRef Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, Vaudry W, Pass RF, Kiell JM, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16–25.CrossRef
9.
go back to reference Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933–43.CrossRef Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933–43.CrossRef
10.
go back to reference Revello MG, Tibaldi C, Masuelli G, Frisina V, Sacchi A, Furione M, Arossa A, Spinillo A, Klersy C, Ceccarelli M, et al. Prevention of primary Cytomegalovirus infection in pregnancy. EBioMedicine. 2015;2(9):1205–10.CrossRef Revello MG, Tibaldi C, Masuelli G, Frisina V, Sacchi A, Furione M, Arossa A, Spinillo A, Klersy C, Ceccarelli M, et al. Prevention of primary Cytomegalovirus infection in pregnancy. EBioMedicine. 2015;2(9):1205–10.CrossRef
11.
go back to reference Daiminger A, Bader U, Eggers M, Lazzarotto T, Enders G. Evaluation of two novel enzyme immunoassays using recombinant antigens to detect cytomegalovirus-specific immunoglobulin M in sera from pregnant women. J Clin Virol. 1999;13(3):161–71.CrossRef Daiminger A, Bader U, Eggers M, Lazzarotto T, Enders G. Evaluation of two novel enzyme immunoassays using recombinant antigens to detect cytomegalovirus-specific immunoglobulin M in sera from pregnant women. J Clin Virol. 1999;13(3):161–71.CrossRef
12.
go back to reference Prince HE, Lape-Nixon M. Role of cytomegalovirus (CMV) IgG avidity testing in diagnosing primary CMV infection during pregnancy. Clin Vaccine Immunol. 2014;21(10):1377–84.CrossRef Prince HE, Lape-Nixon M. Role of cytomegalovirus (CMV) IgG avidity testing in diagnosing primary CMV infection during pregnancy. Clin Vaccine Immunol. 2014;21(10):1377–84.CrossRef
13.
go back to reference Tanimura K, Tairaku S, Ebina Y, Morioka I, Nagamata S, Deguchi K, Morizane M, Deguchi M, Minematsu T, Yamada H. Prediction of congenital Cytomegalovirus infection in high-risk pregnant women. Clin Infect Dis. 2017;64(2):159–65.CrossRef Tanimura K, Tairaku S, Ebina Y, Morioka I, Nagamata S, Deguchi K, Morizane M, Deguchi M, Minematsu T, Yamada H. Prediction of congenital Cytomegalovirus infection in high-risk pregnant women. Clin Infect Dis. 2017;64(2):159–65.CrossRef
14.
go back to reference Giannattasio A, Di Costanzo P, De Matteis A, Milite P, De Martino D, Bucci L, Augurio MR, Bravaccio C, Ferrara T, Capasso L, et al. Outcomes of congenital cytomegalovirus disease following maternal primary and non-primary infection. J Clin Virol. 2017;96:32–6.CrossRef Giannattasio A, Di Costanzo P, De Matteis A, Milite P, De Martino D, Bucci L, Augurio MR, Bravaccio C, Ferrara T, Capasso L, et al. Outcomes of congenital cytomegalovirus disease following maternal primary and non-primary infection. J Clin Virol. 2017;96:32–6.CrossRef
15.
go back to reference Zalel Y, Gilboa Y, Berkenshtat M, Yoeli R, Auslander R, Achiron R, Goldberg Y. Secondary cytomegalovirus infection can cause severe fetal sequelae despite maternal preconceptional immunity. Ultrasound Obstet Gynecol. 2008;31(4):417–20.CrossRef Zalel Y, Gilboa Y, Berkenshtat M, Yoeli R, Auslander R, Achiron R, Goldberg Y. Secondary cytomegalovirus infection can cause severe fetal sequelae despite maternal preconceptional immunity. Ultrasound Obstet Gynecol. 2008;31(4):417–20.CrossRef
16.
go back to reference Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics. 1999;104(1 Pt 1):55–60.CrossRef Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics. 1999;104(1 Pt 1):55–60.CrossRef
17.
go back to reference Wada K, Kubota N, Ito Y, Yagasaki H, Kato K, Yoshikawa T, Ono Y, Ando H, Fujimoto Y, Kiuchi T, et al. Simultaneous quantification of Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6 DNA in samples from transplant recipients by multiplex real-time PCR assay. J Clin Microbiol. 2007;45(5):1426–32.CrossRef Wada K, Kubota N, Ito Y, Yagasaki H, Kato K, Yoshikawa T, Ono Y, Ando H, Fujimoto Y, Kiuchi T, et al. Simultaneous quantification of Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6 DNA in samples from transplant recipients by multiplex real-time PCR assay. J Clin Microbiol. 2007;45(5):1426–32.CrossRef
18.
go back to reference Shigemi D, Yamaguchi S, Otsuka T, Kamoi S, Takeshita T. Seroprevalence of cytomegalovirus IgG antibodies among pregnant women in Japan from 2009-2014. Am J Infect Control. 2015;43(11):1218–21.CrossRef Shigemi D, Yamaguchi S, Otsuka T, Kamoi S, Takeshita T. Seroprevalence of cytomegalovirus IgG antibodies among pregnant women in Japan from 2009-2014. Am J Infect Control. 2015;43(11):1218–21.CrossRef
19.
go back to reference Puhakka L, Renko M, Helminen M, Peltola V, Heiskanen-Kosma T, Lappalainen M, Surcel HM, Lonnqvist T, Saxen H. Primary versus non-primary maternal cytomegalovirus infection as a cause of symptomatic congenital infection - register-based study from Finland. Infect Dis (Lond). 2017;49(6):445–53.CrossRef Puhakka L, Renko M, Helminen M, Peltola V, Heiskanen-Kosma T, Lappalainen M, Surcel HM, Lonnqvist T, Saxen H. Primary versus non-primary maternal cytomegalovirus infection as a cause of symptomatic congenital infection - register-based study from Finland. Infect Dis (Lond). 2017;49(6):445–53.CrossRef
20.
go back to reference Ross SA, Arora N, Novak Z, Fowler KB, Britt WJ, Boppana SB. Cytomegalovirus reinfections in healthy seroimmune women. J Infect Dis. 2010;201(3):386–9.CrossRef Ross SA, Arora N, Novak Z, Fowler KB, Britt WJ, Boppana SB. Cytomegalovirus reinfections in healthy seroimmune women. J Infect Dis. 2010;201(3):386–9.CrossRef
21.
go back to reference Picone O, Grangeot-Keros L, Senat M, Fuchs F, Bouthry E, Ayoubi J, Benachi A, Vauloup-Fellous C. Cytomegalovirus non-primary infection during pregnancy. Can serology help with diagnosis? J Matern Fetal Neonatal Med. 2017;30(2):224–7.CrossRef Picone O, Grangeot-Keros L, Senat M, Fuchs F, Bouthry E, Ayoubi J, Benachi A, Vauloup-Fellous C. Cytomegalovirus non-primary infection during pregnancy. Can serology help with diagnosis? J Matern Fetal Neonatal Med. 2017;30(2):224–7.CrossRef
22.
go back to reference Toriyabe K, Morikawa F, Minematsu T, Ikejiri M, Suga S, Ikeda T. Anti-cytomegalovirus immunoglobulin M titer for congenital infection in first-trimester pregnancy with primary infection: a multicenter prospective cohort study. J Perinatol. 2017;37(12):1272–7.CrossRef Toriyabe K, Morikawa F, Minematsu T, Ikejiri M, Suga S, Ikeda T. Anti-cytomegalovirus immunoglobulin M titer for congenital infection in first-trimester pregnancy with primary infection: a multicenter prospective cohort study. J Perinatol. 2017;37(12):1272–7.CrossRef
23.
go back to reference Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–63.CrossRef Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–63.CrossRef
24.
go back to reference Enders G, Daiminger A, Bader U, Exler S, Enders M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. J Clin Virol. 2011;52(3):244–6.CrossRef Enders G, Daiminger A, Bader U, Exler S, Enders M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. J Clin Virol. 2011;52(3):244–6.CrossRef
25.
go back to reference Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–76.CrossRef Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–76.CrossRef
26.
go back to reference Numazaki K, Fujikawa T. Chronological changes of incidence and prognosis of children with asymptomatic congenital cytomegalovirus infection in Sapporo, Japan. BMC Infect Dis. 2004;4:22.CrossRef Numazaki K, Fujikawa T. Chronological changes of incidence and prognosis of children with asymptomatic congenital cytomegalovirus infection in Sapporo, Japan. BMC Infect Dis. 2004;4:22.CrossRef
27.
go back to reference Fletcher KT, Horrell EMW, Ayugi J, Irungu C, Muthoka M, Creel LM, Lester C, Bush ML. The natural history and rehabilitative outcomes of hearing loss in congenital Cytomegalovirus: a systematic review. Otol Neurotol. 2018;39(7):854–64.CrossRef Fletcher KT, Horrell EMW, Ayugi J, Irungu C, Muthoka M, Creel LM, Lester C, Bush ML. The natural history and rehabilitative outcomes of hearing loss in congenital Cytomegalovirus: a systematic review. Otol Neurotol. 2018;39(7):854–64.CrossRef
28.
go back to reference Foulon I, Naessens A, Foulon W, Casteels A, Gordts F. A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. J Pediatr. 2008;153(1):84–8.CrossRef Foulon I, Naessens A, Foulon W, Casteels A, Gordts F. A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. J Pediatr. 2008;153(1):84–8.CrossRef
29.
go back to reference Lanzieri TM, Chung W, Flores M, Blum P, Caviness AC, Bialek SR, Grosse SD, Miller JA, Demmler-Harrison G. Hearing loss in children with asymptomatic congenital Cytomegalovirus infection. Pediatrics. 2017;139:3.CrossRef Lanzieri TM, Chung W, Flores M, Blum P, Caviness AC, Bialek SR, Grosse SD, Miller JA, Demmler-Harrison G. Hearing loss in children with asymptomatic congenital Cytomegalovirus infection. Pediatrics. 2017;139:3.CrossRef
30.
go back to reference Gantt S, Bitnun A, Renaud C, Kakkar F, Vaudry W. Diagnosis and management of infants with congenital cytomegalovirus infection. Paediatr Child Health. 2017;22(2):72–4.CrossRef Gantt S, Bitnun A, Renaud C, Kakkar F, Vaudry W. Diagnosis and management of infants with congenital cytomegalovirus infection. Paediatr Child Health. 2017;22(2):72–4.CrossRef
31.
go back to reference Marsico C, Kimberlin DW. Congenital Cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr. 2017;43(1):38.CrossRef Marsico C, Kimberlin DW. Congenital Cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr. 2017;43(1):38.CrossRef
32.
go back to reference Lanari M, Lazzarotto T, Venturi V, Papa I, Gabrielli L, Guerra B, Landini MP, Faldella G. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics. 2006;117(1):e76–83.CrossRef Lanari M, Lazzarotto T, Venturi V, Papa I, Gabrielli L, Guerra B, Landini MP, Faldella G. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics. 2006;117(1):e76–83.CrossRef
33.
go back to reference Kawada J, Torii Y, Kawano Y, Suzuki M, Kamiya Y, Kotani T, Kikkawa F, Kimura H, Ito Y. Viral load in children with congenital cytomegalovirus infection identified on newborn hearing screening. J Clin Virol. 2015;65:41–5.CrossRef Kawada J, Torii Y, Kawano Y, Suzuki M, Kamiya Y, Kotani T, Kikkawa F, Kimura H, Ito Y. Viral load in children with congenital cytomegalovirus infection identified on newborn hearing screening. J Clin Virol. 2015;65:41–5.CrossRef
34.
go back to reference Yamaguchi A, Oh-Ishi T, Arai T, Sakata H, Adachi N, Asanuma S, Oguma E, Kimoto H, Matsumoto J, Fujita H, et al. Screening for seemingly healthy newborns with congenital cytomegalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study. BMJ Open. 2017;7(1):e013810.CrossRef Yamaguchi A, Oh-Ishi T, Arai T, Sakata H, Adachi N, Asanuma S, Oguma E, Kimoto H, Matsumoto J, Fujita H, et al. Screening for seemingly healthy newborns with congenital cytomegalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study. BMJ Open. 2017;7(1):e013810.CrossRef
35.
go back to reference Leruez-Ville M, Ghout I, Bussieres L, Stirnemann J, Magny JF, Couderc S, Salomon LJ, Guilleminot T, Aegerter P, Benoist G, et al. In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study. Am J Obstet Gynecol. 2016;215(4):462 e461–10.CrossRef Leruez-Ville M, Ghout I, Bussieres L, Stirnemann J, Magny JF, Couderc S, Salomon LJ, Guilleminot T, Aegerter P, Benoist G, et al. In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study. Am J Obstet Gynecol. 2016;215(4):462 e461–10.CrossRef
Metadata
Title
Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection
Authors
Yuka Torii
Shigeru Yoshida
Yoichiro Yanase
Takashi Mitsui
Kazuhiro Horiba
Toshihiko Okumura
Suguru Takeuchi
Takako Suzuki
Jun-ichi Kawada
Tomomi Kotani
Mamoru Yamashita
Yoshinori Ito
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2019
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-019-2360-1

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