CMV Infection in Mothers and Infants: Diagnostic and Treatment Challenges

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The average transmission rate of maternal primary CMV infection to the fetus is 40%. <i>Photo Credit: CNRI/Science Source.</i>
The average transmission rate of maternal primary CMV infection to the fetus is 40%. Photo Credit: CNRI/Science Source.

Cytomegalovirus (CMV) is the most frequent cause of congenital infection globally and the leading nonhereditary cause of hearing loss in children.1,2 In developed countries, it occurs at a rate of 0.6% to 0.7% of all live births.1 Severe forms of congenital CMV disease often involve multiple organ systems and carry a risk of congenital malformation, developmental delay, or even death in newborns.2

Despite the heavy disease burden, CMV infection is severely underdiagnosed because the majority (approximately 80%) of affected mothers are asymptomatic.3 Diagnosis and treatment are further complicated by the complex nature of the virus, the lack of national screening programs in mothers and infants, and the knowledge gaps concerning the epidemiology of CMV infection.4 In the absence of an effective CMV vaccine, preventive strategies are largely focused on the prevention of maternal infection with behavioral strategies and meticulous hygiene measures.

In an interview with Infectious Disease Advisor, Gail J. Demmler-Harrison, MD, professor of pediatrics, section of infectious diseases, Baylor College of Medicine, and attending physician, infectious disease service, Texas Children's Hospital, in Houston, discussed the diagnostic and treatment challenges of CMV infection in mothers and infants.

Infectious Disease Advisor: What percentage of women who experience CMV infection during pregnancy transmit the infection to their newborn? Is the risk of transmission greater if the mother is experiencing primary infection?

Gail J. Demmler-Harrison, MD: Women who experience CMV infection during pregnancy may transmit the infection to their fetus and newborn. The risk of transmission and congenital CMV infection is greater if the woman is experiencing a primary or first infection with the virus, and ranges from 30% to 55%, with an average of 40% transmission to the fetus after a maternal primary CMV infection.5 Women who experience a recurrent CMV infection, from reactivation or reinfection with CMV during pregnancy, may also transmit the virus to their fetus and newborn, but the risk for transmission is considered much lower than during a primary CMV infection, and usually less than 1%.5   

Infectious Disease Advisor: What treatments are available for pregnant women diagnosed with CMV?

Dr Demmler-Harrison: There are no standard treatments for pregnant women experiencing primary CMV infection to prevent CMV transmission to the fetus. However, administration of CMV hyperimmune globulin in a pregnant woman has been shown in some studies to reduce the risk of transmission of the virus to the fetus,6 and in other studies not to have a significant clinical benefit.7 In addition, some studies have evaluated standard intravenous immune globulin for this same indication.8   

Infectious Disease Advisor: How effective are the available strategies/treatments in preventing the transmission of the virus to the fetus? 

Dr Demmler-Harrison: The prevention of transmission of CMV to the fetus after a maternal primary infection with CMV is a controversial clinical issue.

The American College of Obstetrics and Gynecology and the Society for Maternal – Fetal Medicine recommend antenatal therapy with antivirals or CMV hyperimmune globulin be offered as part of research protocols at this time.9

There are ongoing randomized clinical trials (Clinical Trials.gov identifier: NCT01376778) of CMV hyperimmune globulin administered to women experiencing a primary CMV infection during pregnancy that are trying to address this controversial clinical issue and see if prenatal treatment will reduce CMV transmission to the fetus. In addition, the antiviral agent valacyclovir has been administered to women whose fetus has symptomatic congenital CMV infection, in a non-randomized fashion in published European studies, with some antiviral benefit observed.10 In addition, these is an ongoing clinical trial of valacyclovir in pregnancy being conducted in Israel (Clinical Trials.gov identifier: NCT02351102).

Infectious Disease Advisor: What are the risks associated with severe congenital CMV stemming from the mother's primary infection during pregnancy? What percent of infants are affected by severe congenital CMV?

Dr Demmler-Harrison: Approximately 10% to 15% of babies born with congenital CMV infection as a result of a maternal primary CMV infection during pregnancy may be born with symptoms at birth from the congenital infection.11 Symptomatic congenital CMV also may rarely occur after a maternal recurrent CMV infection. There is a broad range of symptoms associated with congenital CMV infection that range from asymptomatically congenitally infected newborns with no obvious symptoms, newborns with only congenital hearing loss, newborns with mild generalized symptoms involving several organs, to newborns with severe symptoms involving many organ systems, as well as involving the brain and sensory organs. It is also estimated that 8% of newborns with serious congenital CMV disease will die from in utero fetal demise, in the newborn period, or early infancy, from the devastating effects of severe congenital CMV disease.11 

Infectious Disease Advisor: How far is the medical research community from developing an effective CMV vaccine?

Dr Demmler-Harrison: Research on a CMV vaccine began in the 1970s and continues to this day, supported by the efforts of both government and industry. Because of the significant impact of CMV on public health, CMV was deemed a vaccine priority for the 21st century by the Institute of Medicine (now called the National Academy of Medicine). However, a safe and effective licensed CMV vaccine is far away.

Infectious Disease Advisor: What are some of the challenges associated with this effort?

Dr Demmler-Harrison: The combination of the complexity of CMV as a virus, its ability to cause not only a primary but a recurrent infection, its lack of a "rash" like measles or chicken pox or rubella leading to the low public awareness of CMV as an important public health problem, and the lack of collaboration between industry and government in the development of a CMV vaccine, all contribute to our inability to produce an effective CMV vaccine.

Prevention of CMV infection and disease will likely require a very novel, multifaceted approach to achieve, combined with collaboration between a variety of industry sponsors and government agencies.

CMV knowledge vaccine or a CMV information vaccination is another contemporary approach to prevention of CMV infection during pregnancy, endorsed by CMV experts and supported by laws in many states, to reduce congenital CMV infection. The CMV knowledge vaccine has 2 main components: an ounce of CMV awareness and 3 simple hygiene precautions.  

First, women must know CMV exists. Since most women have never heard of CMV, and therefore are not aware that CMV even exists, they cannot take precautions to prevent CMV infection during pregnancy. Secondly, hygiene precautions focused on the most likely source of active CMV infection, that of young children, especially toddlers, who may be actively shedding CMV and transmit the virus to their pregnant mothers, can be practiced. By avoiding sharing food or drink, avoiding kissing toddlers and young children on or near the lips, and washing hands carefully after all diaper changes and wiping runny noses or drool, pregnant women may reduce their risk of acquiring CMV and reduce their risk of congenital CMV infection in their newborn. Until an injectable, "traditional" CMV vaccine is licensed, the CMV knowledge vaccine is the only method for prevention of CMV during pregnancy, at this time. 

References

  1. Marsico C, Kimberlin DW. Congenital cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr. 2017;43(1):38. doi: 10.1186/s13052-017-0358-8 
  2. Naing ZW, Scott GM, Shand A, et al. Congenital cytomegalovirus infection in pregnancy: a review of prevalence, clinical features, diagnosis and prevention. Aust N Z J Obstet Gynaecol. 2016;56(1):9-18. doi: 10.1111/ajo.12408
  3. Kagan KO, Hamprecht K. Cytomegalovirus infection in pregnancy [published online May 15, 2017]. Arch Gynecol Obstet. doi: 10.1007/s00404-017-4380-2
  4. Leruez-Ville M, Magny J-F, Couderc S, 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 [published online April 17, 2017]. Clin Infect Dis. doi: 10.1093/cid/cix337 
  5. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17:253-276. doi: 10.1002/rmv.535
  6. Nigro G, Adler S, La Torre R, et al. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med. 2005;353(13):1350-1362. doi: 10.1056/NEJMoa043337
  7. Revello MG, Lazzarotto T, Guerra B, et al; CHIP Study Group. A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med. 2014;370(14):1316-1326. doi: 10.1056/NEJMoa1310214
  8. Polilli E, Parruti G, D'Arcangelo F, et al. Preliminary evaluation of the safety and efficacy of standard intravenous immunoglobulins in pregnant women with primary cytomegalovirus infection. Clin Vaccine Immunol. 2012;19(12):1991-1993. doi: 10.1128/CVI.00509-12
  9. Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Gyamfi-Bannerman C.  Diagnosis and antenatal management of congenital cytomegalovirus infectionAm J Obstet Gynecol. 2016;214(6):B5-B11. doi: 10.1016/j.ajog.2016.02.042
  10. Jacquemard F, Yamamoto M, Costa JM, et al. Maternal administration of valaciclovir in symptomatic intrauterine cytomegalovirus infection. BJOG. 2007;114(9):1113-1121. doi: 10.1111/j.1471-0528.2007.01308.x
  11. Istas A, Demmler G, Dobbins J, et al. Surveillance for congenital cytomegalovirus disease: A report from the National Congenital Cytomegalovirus Disease Registry. Clin Infect Dis. 1995;29(3):665-670. doi: 10.1093/clinids/20.3.665
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