Takeaway points for pregnant women
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?
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
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
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
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
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
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
- 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
- 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)
Rationale
Population
Need
Rationale
- 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
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
- 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
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
- 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