J Korean Med Sci.  2023 Aug;38(32):e249. 10.3346/jkms.2023.38.e249.

The Multifaceted Clinical Characteristics of Congenital Cytomegalovirus Infection: From Pregnancy to Long-Term Outcomes

• Kim Y
• Kim Ym
• Kim DR
• Kim HG
• Sung JH
• Choi SJ
• Oh Sy
• Kim YJ
• Chang YS
• Kim D
• Kim JS
• Moon IJ
• Roh CR

• KMID: 2545201
• DOI: http://doi.org/10.3346/jkms.2023.38.e249

Abstract

Background
The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a multidisciplinary approach including obstetrics, pediatrics, pathology, and otorhinolaryngology-head and neck surgery.
Methods
This is a retrospective study including 30 consecutive cases of congenital CMV infection that were diagnosed at a single tertiary hospital located in Seoul, Korea from January 2009 to December 2020. Congenital CMV infection was defined as a positive result by polymerase chain reaction from urine, saliva or cerebrospinal fluid or positive CMV IgM from neonatal blood sampled within 3 weeks after birth. All cases were analyzed with respect to whole clinical characteristics from diagnosis to treatment of congenital CMV by a multidisciplinary approach including prenatal sonographic findings, maternal immune status regarding CMV infection, detailed placental pathology, neonatal clinical manifestation, auditory brainstem response test, and antiviral treatment (ganciclovir or valganciclovir). Long-term outcomes including developmental delay and hearing loss were also investigated.
Results
The total number of births during the study period in our institution was 19,385, with the prevalence of congenital infection estimated to be 0.15%. Among 30 cases of congenital CMV, the median gestational age at delivery was 32.2 weeks [range, 22.6–40.0] and 66.7% of these infants were delivered preterm at less than 37 weeks. Suspected fetal growth restriction was the most common prenatal ultrasound finding (50%) followed by ventriculomegaly (17.9%) and abnormal placenta (17.9%), defined as thick placenta with calcification. No abnormal findings on ultrasound examination were observed in one-third of births. Maternal CMV serology tests were conducted in only 8 cases, and one case each of positive and equivocal IgM were found. The most common placental pathologic findings were chronic villitis (66.7%) and calcification (63.0%), whereas viral inclusions were identified in only 22.2%. The most common neonatal manifestations were jaundice (58.6%) followed by elevation of aspartate aminotransferase (55.2%) and thrombocytopenia (51.7%). After excluding cases for which long-term outcomes were unavailable due to death (n = 4) or subsequent follow up loss (n = 3), developmental delay was confirmed in 43.5% of infants (10/23), and hearing loss was confirmed in 42.9% (9/21) during the follow-up period. In our cohort, 56.7% (17/30) of neonates were treated for congenital CMV with ganciclovir or valganciclovir.
Conclusion
Our data show that prenatal findings including maternal serologic tests and ultrasound have limited ability to detect congenital CMV in Korea. Given that CMV is associated with high rates of developmental delay and hearing loss in infants, there is an urgent need to develop specific strategies for the definite diagnosis of congenital CMV infection during the perinatal period by a multidisciplinary approach to decrease the risks of neurologic impairment and hearing loss through early antiviral treatment.

Keyword

Cytomegalovirus; Congenital Infection; Infection Ultrasound; Ganciclovir; Valganciclovir; Developmental Delay; Hearing Loss

Figure

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  Fig. 1 Maternal CMV serology results among abnormal sonographic findings.CMV = cytomegalovirus, N/A = not applicable.

Reference

1. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007; 17(4):253–276. PMID: 17579921.

2. Leruez-Ville M, Ville Y. Fetal cytomegalovirus infection. Best Pract Res Clin Obstet Gynaecol. 2017; 38:97–107. PMID: 27923540.

3. Choi SR, Kim KR, Son S, Kim DS, Chang YS, Cho EY, et al. The prevalence of symptomatic congenital cytomegalovirus disease in Korea; a 15-year multicenter study and analysis of big data from National Health Insurance System. J Pediatric Infect Dis Soc. 2023; 12(2):104–108. PMID: 36399091.

4. Fowler KB, Boppana SB. Congenital cytomegalovirus infection. Semin Perinatol. 2018; 42(3):149–154. PMID: 29503048.

5. 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):355–363. PMID: 17542052.

6. Rawlinson WD, Boppana SB, Fowler KB, Kimberlin DW, Lazzarotto T, Alain S, et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis. 2017; 17(6):e177–e188. PMID: 28291720.

7. Yinon Y, Farine D, Yudin MH. No. 240-cytomegalovirus infection in pregnancy. J Obstet Gynaecol Can. 2018; 40(2):e134–e141. PMID: 29447718.

8. de Vries JJ, van Zwet EW, Dekker FW, Kroes AC, Verkerk PH, Vossen AC. The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model. Rev Med Virol. 2013; 23(4):241–249. PMID: 23559569.

9. Choi R, Lee S, Lee SG, Lee EH. Seroprevalence of CMV IgG and IgM in Korean women of childbearing age. J Clin Lab Anal. 2021; 35(4):e23716. PMID: 33783845.

10. Choi SR, Kim KR, Kim DS, Kang JM, Kim SJ, Kim JM, et al. Changes in cytomegalovirus seroprevalence in Korea for 21 years: a single center study. Pediatr Infect Vaccine. 2018; 25(3):123–131.

11. Kim BJ, Han JJ, Shin SH, Kim HS, Yang HR, Choi EH, et al. Characterization of detailed audiological features of cytomegalovirus infection: a composite cohort study from groups with distinct demographics. BioMed Res Int. 2018; 2018:7087586. PMID: 30228987.

12. Kwak M, Yum MS, Yeh HR, Kim HJ, Ko TS. Brain magnetic resonance imaging findings of congenital cytomegalovirus infection as a prognostic factor for neurological outcome. Pediatr Neurol. 2018; 83:14–18. PMID: 29681488.

13. Grannum PA, Berkowitz RL, Hobbins JC. The ultrasonic changes in the maturing placenta and their relation to fetal pulmonic maturity. Am J Obstet Gynecol. 1979; 133(8):915–922. PMID: 434036.

14. Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical outcome. Clin Infect Dis. 2013; 57(Suppl 4):S178–S181. PMID: 24257422.

15. Lim JS, Lim SW, Ahn JH, Song BS, Shim KS, Hwang IT. New Korean reference for birth weight by gestational age and sex: data from the Korean Statistical Information Service (2008–2012). Ann Pediatr Endocrinol Metab. 2014; 19(3):146–153. PMID: 25346919.

16. Uenaka M, Morizane M, Tanimura K, Deguchi M, Kanzawa M, Itoh T, et al. Histopathological analysis of placentas with congenital cytomegalovirus infection. Placenta. 2019; 75:62–67. PMID: 30712668.

17. Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015; 372(10):933–943. PMID: 25738669.

18. Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis. 2005; 16(1):44–49. PMID: 15685149.

19. Leruez-Ville M, Magny JF, Couderc S, Pichon C, Parodi M, Bussières L, et al. Risk factors for congenital cytomegalovirus infection following primary and nonprimary maternal infection: a prospective neonatal screening study using polymerase chain reaction in Saliva. Clin Infect Dis. 2017; 65(3):398–404. PMID: 28419213.

20. Yamada H, Tanimura K, Fukushima S, Fujioka K, Deguchi M, Sasagawa Y, et al. A cohort study of the universal neonatal urine screening for congenital cytomegalovirus infection. J Infect Chemother. 2020; 26(8):790–794. PMID: 32273174.

21. Hughes BL, Gyamfi-Bannerman C. Society for Maternal-Fetal Medicine (SMFM). Diagnosis and antenatal management of congenital cytomegalovirus infection. Am J Obstet Gynecol. 2016; 214(6):B5–11. PMID: 26902990.

22. Leruez-Ville M, Foulon I, Pass R, Ville Y. Cytomegalovirus infection during pregnancy: state of the science. Am J Obstet Gynecol. 2020; 223(3):330–349. PMID: 32105678.

23. Maltezou PG, Kourlaba G, Kourkouni E, Luck S, Blázquez-Gamero D, Ville Y, et al. Maternal type of CMV infection and sequelae in infants with congenital CMV: systematic review and meta-analysis. J Clin Virol. 2020; 129:104518. PMID: 32622333.

24. Lazzarotto T, Guerra B, Lanari M, Gabrielli L, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. J Clin Virol. 2008; 41(3):192–197. PMID: 18054840.

25. Shahar-Nissan K, Pardo J, Peled O, Krause I, Bilavsky E, Wiznitzer A, et al. Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial. Lancet. 2020; 396(10253):779–785. PMID: 32919517.

26. Jacquemard F, Yamamoto M, Costa JM, Romand S, Jaqz-Aigrain E, Dejean A, et al. Maternal administration of valaciclovir in symptomatic intrauterine cytomegalovirus infection. BJOG. 2007; 114(9):1113–1121. PMID: 17617198.

27. Leruez-Ville M, Ghout I, Bussières L, Stirnemann J, Magny JF, Couderc S, 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.e1–462.10.

28. Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med. 1999; 340(19):1462–1470. PMID: 10320384.

29. Faure-Bardon V, Fourgeaud J, Stirnemann J, Leruez-Ville M, Ville Y. Secondary prevention of congenital cytomegalovirus infection with valacyclovir following maternal primary infection in early pregnancy. Ultrasound Obstet Gynecol. 2021; 58(4):576–581. PMID: 33998084.

30. Chung YS, Oh SH, Park SK. Results of a government-supported newborn hearing screening pilot project in the 17 cities and provinces from 2014 to 2018 in Korea. J Korean Med Sci. 2020; 35(31):e251. PMID: 32776720.

31. Korean Audiological Society, Korean Otologic Society. Korean Clinical Practice Guideline: Newborn Hearing Screening 2010. Seoul: ML Communications;2011. p. 1–80.

32. Park SK, Chang J, Im GJ, Ahn JH, Lee JH, Han KD, et al. Status of early hearing detection and intervention in South Korea: a nationwide population-based study of national infant health checkup. Sci Rep. 2020; 10(1):16838. PMID: 33033313.

33. Nicloux M, Peterman L, Parodi M, Magny JF. Outcome and management of newborns with congenital cytomegalovirus infection. Arch Pediatr. 2020; 27(3):160–165. PMID: 32127242.

34. Pesch MH, Kuboushek K, McKee MM, Thorne MC, Weinberg JB. Congenital cytomegalovirus infection. BMJ. 2021; 373(1212):n1212. PMID: 34083180.

35. 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. PMID: 23297260.

36. Foulon I, Naessens A, Faron G, Foulon W, Jansen AC, Gordts F. Hearing thresholds in children with a congenital CMV infection: a prospective study. Int J Pediatr Otorhinolaryngol. 2012; 76(5):712–717. PMID: 22386305.

37. Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF. Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. J Am Acad Audiol. 2000; 11(5):283–290. PMID: 10821506.

38. Kim JH, Roh KJ, Nam GS, Son EJ. Audiologic status of children with confirmed cytomegalovirus infection: a case series. J Korean Med Sci. 2020; 35(30):e244. PMID: 32743988.

39. Lee SY, Jeon HW, Ahn SY, Oh SH, Kim BJ, Choi BY. Significance of cytomegalovirus tests after three weeks of life in children with hearing loss. Int J Pediatr Otorhinolaryngol. 2023; 168:111555. PMID: 37075593.

40. Townsend CL, Forsgren M, Ahlfors K, Ivarsson SA, Tookey PA, Peckham CS. Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom. Clin Infect Dis. 2013; 56(9):1232–1239. PMID: 23334811.