Keywords
congenital cytomegalovirus - primary CMV infection - CMV hyperimmune globulin - screening
program
Congenital cytomegalovirus (CMV) is the most common cause of congenital infection
in the United States, with a prevalence of 0.64%.[1]
[2] About 1 in every 150 babies born in the United States is infected, with a total
of 30,000 cases each year.[3] Almost 8,000 children are permanently disabled with symptoms such as developmental
delay, deafness, and vision loss each year, and almost 400 die every year as a result
of congenital CMV.[4]
[5] This translates into ∼2 billion dollars spent on CMV-related health care costs per
year in addition to immeasurable emotional burden to those affected.[5]
Given this tremendous impact on society, research in the area of prevention and treatment
of primary maternal CMV infection is a priority. Recent developments for potential
prevention strategies, including CMV-specific hyperimmune globulin (HIG) and hygiene
modification, in addition to new screening tools such as immunoglobulin (Ig) G avidity
assays, make screening for primary maternal CMV infection tempting. However, before
recommending screening for CMV as a routine part of prenatal care, one must consider
whether the test meets established criteria for the introduction of a screening test.
Criteria for Implementation of CMV Screening
Criteria for Implementation of CMV Screening
Due to recent developments in diagnosing and preventing maternal and congenital infection,
there has been some national discussion regarding the issue of screening for primary
maternal infection.[6]
[7] Prior to instituting a formal guideline for screening all pregnant women, it is
important to assess whether key criteria for disease screening are met. The disease
must be clinically important, prevalent, and well characterized. The screening test
must be safe, reliable, and valid. Finally, the intervention must be effective, cost-effective,
and feasible.
Epidemiology
Maternal infection with CMV can be primary or nonprimary. Nonprimary infections may
represent reactivation of a latent infection or reinfection with a new strain of virus.
In reproductive age women, seroprevalence rates range from 40 to 83%.[8]
[9] A primary maternal infection, as evidenced by seroconversion during pregnancy, occurs
in about 1 to 4% of pregnant women, which results in approximately 27,000 cases per
year in the United States.[5]
[10]
[11]
[12] In women with a nonprimary infection, the rate of fetal transmission is 1%.[13] In contrast, the rate of fetal transmission in women who seroconvert during pregnancy
is 30 to 40%.[14] As gestational age increases, the rate of vertical transmission increases. However,
fetal infection early in pregnancy is associated with worse sequelae.[15]
Transmission of CMV occurs through direct contact with the bodily fluids, such as
saliva, urine, or semen, of someone who is actively shedding the virus. For women
of reproductive age, the greatest risk for exposure is through contact with the urine
or saliva of young children.[16] This places women with young children or working in daycare centers at a higher
risk of infection.[17]
Biology of Placental CMV Infection
Biology of Placental CMV Infection
Most immunocompetent women infected with CMV are asymptomatic. If women develop symptoms,
they are usually vague and consist of fever, malaise, myalgias, and chills.[18] Once infected, IgM and IgG antibodies to CMV are produced. The IgM antibody titer
is usually high for the first 1 to 3 months (acute phase) and then declines thereafter
(convalescent phase).[19] IgM antibodies may persist for up to 6 to 9 months after primary infection and may
be present with nonprimary infection.[20] Once the virus is present in the maternal bloodstream, neutralizing antibodies bind
with viral antigen. Neutralizing IgG antibodies are those that bind with high avidity.
Those IgG antibodies with low avidity are indicative of a recent infection and have
poor neutralizing capability. One theory of the mechanism of placental infection is
through transcytosis of a low avidity IgG-virion complex into the syncitiotrophoblast.[21] Low-avidity IgG antibodies are present only with primary infection and may be detectable
for 3 to 5 months after initial exposure.[22] The exact mode of fetal transmission is unknown.
Current Recommendations for Screening
Current Recommendations for Screening
The most recent recommendation from the American College of Obstetricians and Gynecologists
(ACOG) is to not routinely screen patients for CMV. Due to the fact that many women
acquire the infection through contact with young children, ACOG does recommend that
women who are in close contact with young children (mothers or daycare workers) be
educated regarding transmission and hygiene practices to reduce transmission.[18] The Centers for Disease Control (CDC) also does not recommend routine maternal screening.[23] The CDC recommends education regarding hygiene practices aimed at preventing transmission
of the virus, such as washing hands after changing a diaper and not sharing utensils
or food with young children.[24] At this time, there are no high-quality studies demonstrating efficacy of hygiene
measures during pregnancy.
Screening Tests for Primary CMV Infection
Screening Tests for Primary CMV Infection
The gold standard for diagnosis of a primary infection is demonstration of seroconversion
with CMV IgG antibodies.[22] Since routine screening in low-risk women is not routinely recommended, seroconversion
is rarely documented. Screening with serial titers is not feasible because it would
require monthly blood tests on every seronegative pregnant woman.
Primary infection may also be suspected by the presence of CMV IgM antibodies. If
IgM antibodies are present, the infection may be acute. However, they may also be
present in the convalescent phase or nonprimary infections. In addition, false-positive
results can occur as a result of cross-reactivity with other disease entities, such
as parvovirus B19 or systemic lupus erythematosus. There are several commercially
available diagnostic kits for CMV IgM and none are standardized for antigen composition.
Therefore, discrepant results can occur among the different testing kits.[25]
[26]
[27]
With such uncertainty surrounding a positive IgM, it can be difficult to determine
whether an infection is primary. Recently, the IgG avidity test has become available
and is able to detect an acute infection with 92 to 100% sensitivity and 82 to 100%
specificity.[20] When combined with a true positive IgM, a low/moderate IgG avidity test has the
same diagnostic value as seroconversion.[20]
The avidity test determines whether the IgG antibody has high avidity, indicating
previous infection, or low avidity, indicating a primary infection. It takes about
18 to 20 weeks for the IgG antibody to demonstrate high avidity after an acute infection.
Therefore, a low avidity test prior to the 18th to 20th weeks of pregnancy can identify
those women at high risk of severe congenital infection.[20] Using the approach of a one-time test, either with an initial serology screen or
not, would be more feasible and cost-effective than serial IgG testing.
Intervention
The ideal intervention for prevention of congenital CMV would be a vaccine. However,
an effective and safe vaccine is still years away from reality, so efforts at prevention
have also focused on maternal education regarding hygiene and potential treatment
with CMV HIG.
Given that congenital CMV infection affects more babies than Down syndrome, neural
tube defects, or fetal alcohol syndrome, one may think the general public would be
aware of its presence. A recent survey by Cannon et al[16] suggests otherwise. Only 13% of women and 7% of men surveyed had heard of congenital
CMV. Given that transmission of the virus is through contact with bodily fluids, educating
pregnant women regarding the mode of transmission and hygiene practices that may prevent
viral acquisition seems plausible as a means to reduce maternal infection.
There have been preliminary studies examining hygiene modification.[28]
[29]
[30] In 1996, Adler et al evaluated 36 nonpregnant and pregnant seronegative women who
received education, education with documented adherence, or no education.[28] Although the sample size was insufficient to show a benefit of education, none of
the pregnant women in either education group seroconverted. This study suggested that
pregnant women may be more motivated to modify behavior in an attempt to avoid infection.
In 2004, Adler again evaluated pregnant and nonpregnant seronegative women randomized
to behavior modification versus control.[29] Although there was no difference in seroconversion rates between the two groups,
educated pregnant women again were less likely to become infected than their nonpregnant
counterparts. Picone et al performed a prospective cohort study of high-risk, seronegative
women and the impact of education and hygiene information.[30] Although there were low rates of seroconversion, there was no control group. Currently,
there are inadequate data to show that education actually changes behavior and that
this behavior change translates into decreasing maternal infection and subsequent
congenital infection.
A second topic of research regarding prevention of congenital disease is aimed at
prevention of maternal-fetal transmission. There have been preliminary results to
suggest that treatment with HIG after documentation of a primary maternal infection
may reduce the risk of congenital infection. A nonrandomized study by Nigro et al
of 181 women with primary infection demonstrated the potential for HIG to be used
as a means of prevention of fetal infection.[31] The prevention group consisted of 37 women who did not undergo amniocentesis because
of gestational age < 20 weeks or proximity of diagnosis (within 6 weeks of primary
infection), or they simply declined. This group was offered 100 U/kg of HIG every
month until delivery. The comparison group was 47 women who did not undergo amniocentesis
but also declined prevention therapy. In the prevention group, 16% of infants whose
mothers received HIG had congenital infection versus 40% of infants in the group declining
HIG. However, controversy exists regarding the heterogeneity of the prevention group,
lack of randomization, and small sample size of this study.
Recently, preliminary data from a randomized trial of CMV HIG for prevention was negative,
with a 44% rate of congenital infection in the placebo group versus 30% rate in the
treatment group (p = 0.13).[32] The full results have not yet been published. There is also one other large, multicenter
randomized trial underway in the United States by the Maternal-Fetal Medicine Units
Network, which is expected to complete enrollment in 2016 (“A Randomized Trial to
Prevent Congenital Cytomegalovirus Infection,” ClinicalTrials.gov#NCT01376778). Until completion of this trial, it is not known whether CMV HIG is effective or
safe.
Conclusion
Congenital CMV is a major public health problem. Efforts at reducing the rate of infection
are a top priority of obstetric research. Although significant advancements have been
made, there are still several knowledge gaps regarding intervention. In this age of
scrutiny regarding public health policies and the cost-effectiveness of screening
and intervention, care must be taken to fully evaluate a screening program with regard
to the disease, the test, and the intervention prior to full implementation.
In the case of CMV, several conditions have been met, although others remain missing.
The disease itself is clinically important, well defined, and prevalent. Due to years
of diagnosis without an available treatment, the natural history is known, with substantial
morbidity/mortality if left untreated. In addition, the development of the avidity
assay has made it possible to detect asymptomatic disease.
With evidence that the disease fulfills criteria for screening, the next step is to
evaluate the screening test itself. The screening technique of using either seroconversion
or IgG, IgM antibodies in addition to IgG avidity is well described. The test is itself
is safe and reliable. It is not known at this time whether it would be accepted by
pregnant women. Given that such a small percentage of the population is even aware
of this condition, maternal perception of the risks and benefits of screening and
treatment cannot be adequately assessed at this time.
The final consideration regarding a screening program is the cost-effectiveness and
feasibility of the proposed intervention. A recent cost-effectiveness model by Cahill
et al examined possible screening strategies for primary maternal infection.[6] Universal screening, screening in high-risk women, screening with fetal findings
on ultrasound, and a baseline reference of no screening or treatment were compared.
Using decision analysis models to assess neonatal outcomes with CMV HIG treatment,
universal screening appeared to be the most cost-effective strategy. However, these
findings are not based on data from a randomized controlled trial. More studies regarding
cost-effectiveness are needed once the current trials are completed.
Screening tests for maternal primary infection of CMV have improved over the last
decade, and if employed in the correct manner, could be used in a very cost-efficient
way. However, screening programs would have to be developed once treatment is shown
to be effective. For example, if a large-scale trial of seronegative pregnant women
demonstrated the effectiveness of behavior modification at preventing maternal acquisition,
serological screening early in pregnancy would be rational. In addition, if the CMV
HIG proves itself to be safe and effective at preventing vertical transmission, testing
for primary maternal infection with antibodies and IgG avidity in the second trimester
has proven reliable in identifying those at risk. However, neither of these interventions
has proven to be effective in large randomized trials, and neither should be accepted
as standard of care until shown to be effective and safe. In the meantime, the recommendations
of ACOG and the CDC should be followed. We should continue to educate those at risk
about the virus and test those with symptoms of active disease. It is not yet time
for universal serum screening for maternal CMV infection.
