Review
Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy

https://doi.org/10.1016/S1473-3099(17)30143-3Get rights and content

Summary

Congenital cytomegalovirus is the most frequent, yet under-recognised, infectious cause of newborn malformation in developed countries. Despite its clinical and public health importance, questions remain regarding the best diagnostic methods for identifying maternal and neonatal infection, and regarding optimal prevention and therapeutic strategies for infected mothers and neonates. The absence of guidelines impairs global efforts to decrease the effect of congenital cytomegalovirus. Data in the literature suggest that congenital cytomegalovirus infection remains a research priority, but data are yet to be translated into clinical practice. An informal International Congenital Cytomegalovirus Recommendations Group was convened in 2015 to address these questions and to provide recommendations for prevention, diagnosis, and treatment. On the basis of consensus discussions and a review of the literature, we do not support universal screening of mothers and the routine use of cytomegalovirus immunoglobulin for prophylaxis or treatment of infected mothers. However, treatment guidelines for infected neonates were recommended. Consideration must be given to universal neonatal screening for cytomegalovirus to facilitate early detection and intervention for sensorineural hearing loss and developmental delay, where appropriate. The group agreed that education and prevention strategies for mothers were beneficial, and that recommendations will need continual updating as further data become available.

Introduction

Many adverse fetal and neonatal outcomes have been prevented since the introduction of maternal screening for infectious diseases during pregnancy, and since the institution of routine rubella vaccination of women of reproductive age. In stark contrast, congenital cytomegalovirus infection remains largely unrecognised in the developed and developing world.1 This is despite congenital cytomegalovirus now being the major infectious cause of sensorineural hearing loss and neurodevelopmental abnormalities in infants born in developed countries,2 and second only to cerebral palsy in all causes of serious malformation in many parts of the world. The prevalence of congenital cytomegalovirus has been reported as 0·2% to 2·0% (average of 0·64%) of pregnancies.3 Many factors contribute to congenital cytomegalovirus mortality and morbidity, including the limited awareness of clinicians and parents about infection during pregnancy, low levels of routine testing of neonates at risk, the absence of maternal or neonatal screening programmes, the limited efficacy and toxicity of current treatments, and the absence of licensed vaccines. In part, because of these limitations, congenital cytomegalovirus and preventive measures for acquiring cytomegalovirus during pregnancy are not routinely or consistently discussed with pregnant women or women attempting conception. However, with evidence for efficacy of preventive actions,4 efficacy of early intervention for children with sensorineural hearing loss,5 evolving antiviral treatments, and recent availability of candidate vaccines for pregnant women and neonates,6 there is an emerging consensus that more attention must be directed to this infection by clinicians3, 7 researchers, and communities. In some states of the USA, legislation requires cytomegalovirus education as part of routine antenatal care.8, 9, 10

To assist with clinical care, an informal International Congenital Cytomegalovirus Recommendations Group was convened as part of the 5th International Congenital Cytomegalovirus conference on April 19, 2015, to review and grade available evidence, and to draft recommendations that could be used to guide congenital cytomegalovirus diagnosis, prevention, and therapy. The International Congenital Cytomegalovirus Recommendations Group addressed whether pregnant women should be screened to aid diagnosis of maternal cytomegalovirus infection, and also addressed methods for diagnosis of maternal or fetal cytomegalovirus infection. Suggestions about who should be educated about congenital cytomegalovirus infections, and preventive measures for maternal cytomegalovirus infection, were considered. Whether cytomegalovirus hyperimmunoglobulin or antiviral therapy could be used routinely to prevent or treat congenital cytomegalovirus infection during pregnancy was discussed. Neonatal screening and the important questions of whether to treat infected neonates, and what form this therapy should consist of, were also addressed.

Section snippets

Methods to provide global recommendations on cytomegalovirus prevention, diagnosis, and treatment

Expert clinicians, opinion leaders for congenital cytomegalovirus, researchers with expertise in congenital cytomegalovirus infection, and representatives of the congenital cytomegalovirus community from Europe, the USA, and Australia were identified and invited to a workshop, organised as part of the 5th International Congenital Cytomegalovirus Conference in Brisbane, Australia (April 19, 2015). Identification of relevant participants was on the basis of publication track records about

Screening for maternal cytomegalovirus infection

Universal cytomegalovirus screening of pregnant women is not recommended by national public health bodies in any country. However, selective testing of pregnant women is done as part of population-based studies, and by some clinicians independently of formal screening programmes in parts of Europe, Israel, Australia, and the USA.15, 16, 17

One proposed approach to reducing the incidence of congenital cytomegalovirus infection is universal cytomegalovirus screening of pregnant women to assist

Conclusions

This Review summarises current data on the efficacy of prevention, the significant improvements in diagnostic capacity globally (particularly in molecular detection and characterisation of infection), and data showing utility of antiviral therapy in some infected neonates. These, and other published data, can now be used to inform jurisdictional policy, and practice, in reducing the global impact of congenital cytomegalovirus.

Search strategy and selection criteria

We published a systematic review on this topic before the meeting, which informed the consensus discussions at the April 2015 conference. Additionally, before this conference, additional relevant scientific literature was identified through searches of MEDLINE, Embase and ClinicalTrials.gov for articles published from Jan 1, 1968 to Feb 28, 2015, and updated after the meeting to Oct 31, 2016. Search terms included “congenital cytomegalovirus” and “treatment”, “screening”, “therapeutic”,

References (139)

  • G Nigro et al.

    Clinical manifestations and abnormal laboratory findings in pregnant women with primary cytomegalovirus infection

    BJOG

    (2003)
  • T Lazzarotto et al.

    Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy

    Clin Microbiol Infect

    (2011)
  • G Enders et al.

    The value of CMV IgG avidity and immunoblot for timing the onset of primary CMV infection in pregnancy

    J Clin Virol

    (2013)
  • LJ Salomon et al.

    MRI and ultrasound fusion imaging for prenatal diagnosis

    Am J Obstet Gynecol

    (2013)
  • C Liesnard et al.

    Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk

    Obstet Gynecol

    (2000)
  • MG Revello et al.

    Pathogenesis and prenatal diagnosis of human cytomegalovirus infection

    J Clin Virol

    (2004)
  • AZ Azam et al.

    Prenatal diagnosis of congenital cytomegalovirus infection

    Obstet Gynecol

    (2001)
  • T Lazzarotto et al.

    Prenatal indicators of congenital cytomegalovirus infection

    J Pediatr

    (2000)
  • B Guerra et al.

    Prenatal diagnosis of symptomatic congenital cytomegalovirus infection

    Am J Obstet Gynecol

    (2000)
  • M Leruez-Ville et al.

    Feasibility of predicting the outcome of fetal infection with cytomegalovirus at the time of prenatal diagnosis

    Am J Obstet Gynecol

    (2016)
  • B Guerra et al.

    Ultrasound prediction of symptomatic congenital cytomegalovirus infection

    Am J Obstet Gynecol

    (2008)
  • S Gerber et al.

    Prenatal diagnosis of congenital cytomegalovirus infection by detection of immunoglobulin M antibodies to the 70-kd heat shock protein in fetal serum

    Am J Obstet Gynecol

    (2002)
  • DI Bernstein et al.

    Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: a randomized clinical trial

    Vaccine

    (2016)
  • J Grosjean et al.

    Human cytomegalovirus quantification in toddlers saliva from day care centers and emergency unit: a feasibility study

    J Clin Virol

    (2014)
  • SL Lim et al.

    Awareness of and attitudes toward congenital cytomegalovirus infection among pregnant women in Singapore

    Int J Gynaecol Obstet

    (2012)
  • MJ Cannon et al.

    Awareness of and behaviors related to child-to-mother transmission of cytomegalovirus

    Prev Med

    (2012)
  • HR Baer et al.

    Survey of congenital cytomegalovirus (cCMV) knowledge among medical students

    J Clin Virol

    (2014)
  • AM Korver et al.

    Awareness of congenital cytomegalovirus among doctors in the Netherlands

    J Clin Virol

    (2009)
  • AG Cordier et al.

    Awareness and knowledge of congenital cytomegalovirus infection among health care providers in France

    J Clin Virol

    (2012)
  • A von Gartzen et al.

    An email survey of midwives knowledge about CytoMegaloVirus (CMV) in Hannover and a skeletal framework for a proposed teaching program

    Nurse Educ Pract

    (2013)
  • MM Mussi-Pinhata et al.

    Birth prevalence and natural history of congenital cytomegalovirus infection in a highly seroimmune population

    Clin Infect Dis

    (2009)
  • A Kenneson et al.

    Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection

    Rev Med Virol

    (2007)
  • S Manicklal et al.

    The “silent” global burden of congenital cytomegalovirus

    Clin Microbiol Rev

    (2013)
  • ST Hamilton et al.

    Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review

    Rev Med Virol

    (2014)
  • AM Korver et al.

    Newborn hearing screening vs later hearing screening and developmental outcomes in children with permanent childhood hearing impairment

    JAMA

    (2010)
  • DW Kimberlin et al.

    Valganciclovir for symptomatic congenital cytomegalovirus disease

    N Engl J Med

    (2015)
  • Hawaii House Bill 782

  • Cytomegalovirus (CMV) public health initiative

  • Texas Senate Bill 791

  • CN Kotton et al.

    International consensus guidelines on the management of cytomegalovirus in solid organ transplantation

    Transplantation

    (2010)
  • The Oxford Levels of Evidence

  • M Forsgren

    Prevention of congenital and perinatal infections

    Euro Surveill

    (2009)
  • G Rahav

    Congenital cytomegalovirus infection—a question of screening

    Isr Med Assoc J

    (2007)
  • S Doutre

    Reducing congenital cytomegalovirus infection through policy and legislation in the United States

    Microbiology Australia

    (2015)
  • SP Walker et al.

    Cytomegalovirus in pregnancy: to screen or not to screen

    BMC Pregnancy Childbirth

    (2013)
  • SP Adler et al.

    Prevention of child-to-mother transmission of cytomegalovirus by changing behaviors: a randomized controlled trial

    Pediatr Infect Dis J

    (1996)
  • SP Adler

    Cytomegalovirus and child day care: risk factors for maternal infection

    Pediatr Infect Dis J

    (1991)
  • BF Walmus et al.

    Factors predictive of cytomegalovirus immune status in pregnant women

    J Infect Dis

    (1988)
  • LH Taber et al.

    Acquisition of cytomegaloviral infections in families with young children: a serological study

    J Infect Dis

    (1985)
  • S Stagno et al.

    Factors associated with primary cytomegalovirus infection during pregnancy

    J Med Virol

    (1984)
  • Cited by (529)

    View all citing articles on Scopus
    View full text