CDC Science Ambassadors--Epidemiology of CMV

Takeaway points for pregnant women

Prenatal screening

Thank you for your attention!

Who has CMV?

Factors associated with CMV seroprevalence worldwide

Review

1999-2004 CMV Seroprevalence in the US

CMV seroprevalence among pregnant women

Seroprevalence is higher among:

• Older people
• Females
• Mexican Americans
• Non-Hispanic Blacks

Seroprevalence is generally higher in developing countries, but some developed countries have high seroprevalence

• How many U.S. children are born with congenital CMV infection each year?
• What are acute symptoms of congenital CMV infection?
• What types of disabilities can congenital CMV cause?
• How many U.S. children have congenital CMV-related disabilities each year?
• What other disabilities have a comparable disease burden?

Bate, CID, 2010

Cannon, Schmid, Hyde, Rev Med Virol, 2010

Biology of transmission

Cytomegalovirus (CMV)

Primary infection

• Member of the Herpesvirus family
• Very large (~240 kb), linear DNA genome

Latency

Most Cost-Effective Vaccine

1999 Institute of Medicine Report

Reactivation

Reinfection

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Impact of congenital CMV

Non-primary or recurrent infection

Risk factors for seropositivity

• Melanoma
• Multiple sclerosis
• Mycobacterium tuberculosis
• Neisseria gonorrhea
• Neisseria meningitidis B
• Parainfluenza
• Respiratory syncytial virus
• Rheumatoid arthritis
• Rotavirus
• Shigella
• Streptococcus, group A
• Streptococcus, group B
• Streptococcus pneumoniae

Transmission of CMV

Costs > $1 billion in direct medical care each year in the U.S.

(Institute of Medicine, 2000)

• Borrelia burgdorferi
• Chlamydia
• Coccidioides immites
• Cytomegalovirus
• Enterotoxigenic E. coli
• Epstein-Barr virus
• Helicobacter pylori
• Hepatitis C virus
• Herpes simplex virus
• Histoplasma capsulatum
• Human papillomavirus
• Influenza
• Type I Diabetes

Relative Burden of Congenital CMV

Risk factors for seroconversion

Long-term sequelae

Estimated Annual Congenital CMV Disease Burden in US

Adapted from Cannon & Davis, BMC Public Health, 2005

• 30,000-40,000 congenital CMV infections
• 3,500 symptomatic infections
• 140 deaths
• >5500 children with permanent sequelae

Dollard, Rev Med Virol, 2007

Risk factors for viral shedding

1. CMV is not transmitted easily

2. Close contact with bodily fluids is required, especially urine and saliva

3. Young children are a major source of infection

4. CMV can be transmitted through sexual activity

CMV during pregnancy

Pregnancy and transmission

Congenital CMV in children with hearing loss

Hearing loss in children with congenital CMV

Sequelae in infected children

Why is CMV a problem?

Congenital CMV Infection

Immunosuppression

• HIV

• Organ transplants

Primary vs non-primary infection

Children Affected by Congenital CMV

Child with cerebral palsy, hearing loss, and mental retardation

The Epidemiology and Prevention of Congenital Cytomegalovirus (CMV) Infection and Disease

Infant with microcephaly

Takeaway points for pregnancy and congenital infection

1. Non-primary infection is the major source of congenital infection

2. Congenital infection occurs in 0.5%-1% of newborns

3. Disabilities occur or develop in 15%-20% of infected newborns

4. Congenital CMV is a major cause of childhood hearing loss

Child with spastic quadraplegic cerebral palsy, vision loss, microcephaly, intracranial calcifications, and epilepsy

Child with hearing loss

Atherosclerosis?

• Rosenfeld, Thrombosis and Haemostatis, 2011

Immunosenescence?

• Brunner, Ageing Res Rev, 2011
• Pawelec, Virus Res, 2011

Review

• What are the demographic risk factors associated with CMV infection?
• Explain the biology of CMV infection--primary infection, latency, etc.
• What behaviors are associated with CMV infection?
• Where is CMV located in the body?
• Explain the major routes of CMV infection.
• Do most newborns get infected through primary or non-primary maternal infections?
• What proportion of infected newborns develop disabilities?
• What proportion of childhood hearing loss is associated with congenital CMV infection?

CMV awareness

Congenital CMV is an Invisible Disease

• Mothers do not know when they are infected
• Many infected babies are asymptomatic at birth
• When babies have symptoms, they are often non-specific
• Congenital CMV usually cannot be diagnosed retrospectively

OB/GYNs aren't talking about it

• Most OB/GYNs don’t counsel pregnant women about CMV

MMWR, Jan. 25, 2008

Few women have heard of congenital CMV in the U.S.

14%

Ross, J Womens Health, 2008

Same study design

Similar study population

2005 vs. 2010

• Lowest awareness of all conditions
• No increase in awareness over time

Pediatricians aren't aware of it

Cannon, Prev Med, 2012

If I had a nickel for every time a pediatrician told me he has never seen congenital CMV...

Or in Singapore

Awareness among pregnant women: 20%

France is better

Lim, Int J Gynecol Obstet, 2012

Unfortunate

but

also

Opportunity

And one more thing...

Clinical and public health approaches already exist that have the potential to substantially reduce the disease burden of congenital CMV...but they need to be tried and evaluated.

Potential clinical and public health measures

Conclusion

Need

• Prenatal screening is not common in the U.S.
• CMV IgM and IgG avidity tests need to be improved, standardized
• Type-specific serologic tests need commercialization

Population and frequency

Need

• Pregnant women
• Repeat testing during pregnancy

~4 million/year in U.S.

• Communication products for women and healthcare providers
• Increased awareness
• Pilot studies to identify effective interventions

Population

Rationale

Need

• Pregnant women

~4 million/year

• Prenatal screening and follow-up can identify most primary infections (Lazzarotto, Clin Microbiol Newsletter, 2010)
• Identification of primary infection would allow for treatment and prenatal diagnosis
• Type-specific serologic tests could identify reinfections (Ross, JID, 2010)
• Knowledge of serostatus may be a key motivator of behavioral change (Picone, BJOG, 2009; Vauloup-Fellous, J Clin Virol, 2009)
• Prenatal screening has pros and cons

• Newborn screening is not common in the U.S.
• Need for accurate, reliable, high-throughput, inexpensive assays
• Case for newborn screening needs to be made

Early detection

and intervention

Rationale

Population

• All newborn children

~4,000,000/year in U.S.

• CMV transmission routes are well-established (Hyde, RMV, 2010; Cannon, RMV, 2011)
• CMV transmission during pregnancy is not inevitable--in fact, it is infrequent even in women with risky exposures (Hyde, RMV, 2010)
• Evidence that behavioral interventions can be successful (Adler, PIDJ, 1996; Picone, BJOG, 2009; Vauloup-Fellous, J Clin Virol, 2009)

Behavioral interventions

Rationale

Population

Need

Rationale

• All newborn children

~4,000,000/year in U.S.

• Newborn CMV screening consists of testing for CMV using viral cultures or CMV DNA using PCR (Grosse, J Clin Virol, 2009)
• Requires urine or saliva obtained within 2 weeks of birth. Dried blood spots may also be used, but sensitivity is poorer.
• The intent is to improve outcomes through early detection and intervention.
• Interventions may be pharmaceutical or non-pharmaceutical.

• Newborn CMV screening is not common in the U.S.
• Need infrastructure for testing, follow-up, intervention services

Paixao, Eur J Pediatr, 2012

• Children who pass newborn hearing screening but who develop CMV-related delayed hearing loss can benefit from monitoring and early intervention services (Grosse, J Clin Virol, 2009)
• Early detection and intervention also likely to help those with cognitive deficit and vision impairment

Prenatal diagnosis

Newborn screening

Need

• Prenatal diagnosis is not common in the U.S. because prenatal screening is not common
• Better prognostic indicators need to be developed

Population

• Pregnant women who have a primary CMV infection

~30,000/year in U.S.

• Pregnant women who have a CMV reinfection?

~40,000/year in U.S.?

Rationale

Treatment to prevent

childhood disease

Vaccination

• Prenatal diagnosis typically refers to invasive testing to determine whether the fetus has CMV infection (Revello, Clin Microbiol Rev, 2002)
• Consists of amniocentesis or fetal blood sampling
• Should take place no sooner than 21 weeks gestation and at least 6 weeks after primary infection (Revello, J Clin Virol, 2011)
• May also include ultrasound or MRI evaluations (Benoist, BJOG, 2008)

• Parents can be prepared for the possibility of a disabled child
• Allows for consideration of treatment

Treatment to prevent

fetal disease

Treatment to prevent

fetal infection

Need

Rationale

Population

Rationale

Need

69% protection against

fetal infection

Maternal seropositivity

(Fowler, JAMA, 2003)

In the U.S. each year congenital CMV:

• Causes disabilities in nearly 6,000 children
• Is one of the major causes of childhood disability
• Costs > $1 billion in direct medical care
• Worldwide burden is similar

• No licensed vaccine
• Could prevent:
• maternal infection
• congenital infection
• congenital disease

• Young children
• Adolescents
• Women of reproductive age

~4 million/year in U.S.

Population

Rationale

Need

• IV ganciclovir and oral valgancyclovir have significant toxicities, especially neutropenia
• Less toxic drugs are needed

gB subunit vaccine reduces maternal infection by 50% during 1st year

(Pass, NEJM, 2009)

Population

Rationale

Need

• Infants with symptomatic congenital CMV with central nervous system (CNS) manifestations had better hearing and developmental outcomes if treated with 6 weeks IV ganciclovir (Kimberlin, J Peds, 2003)
• Trial underway to treat infants with symptomatic congenital CMV with 6 months of oral valgancyclovir (Kimberlin, JID, 2008).

• Children with symptomatic congenital CMV and CNS manifestations

~2,000/year in U.S.

• Children with symptomatic congenital CMV and no CNS manifestations?

~4,000/year in U.S.?

• Pregnant women with primary CMV infections were significantly less likely to transmit CMV to fetuses when treated with CMV hyperimmune globulin (HIG) (Nigro, NEJM, 2005)

gB subunit vaccine reduces duration of viremia in organ transplant recipients (Griffiths, Lancet, 2011)

• Pregnant women who have an infected fetus

~30,000/year in U.S.

• Unclear if CMV HIG is effective--3 trials currently underway
• Other treatments (e.g., monoclonal antibodies, valacyclovir) have not been tested for the prevention of fetal infection

• Pregnant women who have a primary CMV infection

~30,000/year in U.S.

• Pregnant women who have a CMV reinfection?

~40,000/year in U.S.?

• Pregnant women with CMV-infected fetuses were significantly less likely to be symptomatic at birth or develop disabilities when treated with CMV hyperimmune globulin (HIG) (Nigro, NEJM, 2005)
• Treatment with valacyclovir led to lower viral loads in fetuses infected by CMV (Jacquemard, BJOG, 2008).

• Unclear if CMV HIG is effective--no trials currently underway
• Unclear if valacylovir prevents CMV-related disease--1 trial currently underway
• Other treatments (e.g., monoclonal antibodies) have not been tested for the prevention of CMV-related disease

Birth

21-22 weeks

Conception

1st prenatal visit

End 1st trimester

End 2nd trimester

Maternal Administration of Valaciclovir in Symptomatic CMV Infection (Jacquemard et al., BJOG 2007)

• Pregnant women with CMV-infected symptomatic fetuses received oral valaciclovir
• Valaciclovir treatment
• Appeared to be safe
• Reached therapeutic concentrations in maternal and fetal compartments
• Reduced viral load in fetal blood
• Limitations
• Not a randomized, controlled trial
• Study not designed to assess disease outcomes in children
• Selection biases could have affected results

3. Diagnosis of congenital CMV

• Cons
• Prenatal CMV diagnosis does not reliably predict whether disability will occur
• Newborn screening can reliably identify congenital CMV in essentially all instances

Passive Immunization during Pregnancy (Nigro et al., NEJM 2005)

• Pros
• Prenatal diagnosis can reliably identify congenital CMV in most instances
• Parents can be prepared for the possibility of a disabled child

• Pregnant women received intravenous CMV hyperimmune globulin (HIG).
• Treatment was safe.
• Hyperimmune globulin associated with:
• Lower risk of congenital CMV infection
• Lower risk of congenital CMV disease
• Limitations
• Not a randomized, controlled trial
• Biggest question: How could physical damage to fetuses, clearly documented in some by ultrasound, be reversed by the antibody treatment, given that the mothers' own CMV antibodies don't always protect fetuses from infection?

Standard of Care Regarding Fetal Chromosomal Abnormalities

Hygienic Practices for Pregnant Women to Reduce Risk of CMV Infection

1. Therapeutic treatment with hyperimmune globulin or antivirals

Goal is either to prevent fetal infection in women with primary infection or prevent disease in infected fetuses (identified because of maternal primary infection)

• Cons
• Most fetal infections will be missed
• Effectiveness of treatments is controversial
• Treatments can be very expensive

Cannon & Davis, BMC Public Health, 2005

• Pros
• Most primary infections and associated fetal infections can be identified
• Experimental treatments exist

Prenatal screening is already offered for conditions (e.g. Down syndrome) for which the utility may be less

Preventing Infection During Pregnancy

Possible Goals of CMV Prenatal Screening

Utility

• The Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) have recommended that physicians counsel women on the prevention of CMV infection during pregnancy.

• Therapeutic treatment with hyperimmune globulin or antivirals
• Primary prevention through education and behavioral change
• Diagnosis of congenital CMV
• Enhanced reproductive decision making

ACOG Practice Bulletin, Sept. 2000; MMWR, Jan. 25, 2008

Which goals currently provide a justifiable rationale for prenatal CMV screening?

2. Primary prevention through education and behavioral change

• Cons
• CMV seropositive women should also practice hygienic measures to prevent re-infection. Screening might give a false sense of security
• Screening is more expensive than simply providing the prevention message to all women

• Pros
• CMV screening will give providers an opportunity to discuss CMV prevention
• CMV seronegative result may motivate women to more carefully practice hygienic measures

• Cons
• Prenatal screening will still leave considerable uncertainty about whether the child will experience permanent disabilities
• Termination of pregnancy will occur for some children who would never experience CMV-related health problems

4. Enhanced reproductive decision making

• Pros
• Prenatal diagnosis can reliably identify congenital CMV in most instances
• Parents can be prepared for the possibility of a disabled child
• Parents can enroll in trials of experimental therapies
• Parents can choose whether to test and whether to terminate the pregnancy