Cytomegalovirus (CMV) congenital infection affects 0.7% of live births worldwide and is the leading cause of congenital neurological handicap of infectious origin. However, systematic screening for this infection has not been implemented in pregnancy or at birth in any country. This apparent paradox had been justified by persisting gaps in the knowledge of this congenital infection: uncertain epidemiological data, difficulty in the diagnosis of maternal infection, absence of validated prenatal prognostic markers, unavailability of an efficient vaccine and scarcity of data available on the treatment. However, in the last decade, new data have emerged towards better management of this congenital infection, including solid epidemiological data, good evidence for the accuracy of diagnosis of maternal CMV infection and good evidence for the feasibility of predicting the outcome of fetal infection by a combination of fetal imaging and fetal laboratory parameters. There is also some evidence that valaciclovir treatment of mothers carrying an infected fetus is feasible, safe and might be effective. This review provides an update on the evidence for diagnosis, prognosis and treatment of congenital infection in the antenatal period. These suggest a benefit to a proactive approach for prenatal congenital infections.
Highlights
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Recent data highlight the true burden of non-primary maternal infection in congenital CMV infection.
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Accurate diagnosis of maternal primary infection is achievable.
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Diagnosis of fetal infection by amniocentesis is reliable.
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Establishing the prognosis of an infected fetus is achievable with over 90% positive and negative predictive values.
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First successful non-randomized study using valaciclovir for symptomatic fetuses.
Epidemiology of CMV fetal infection
The epidemiology of congenital cytomegalovirus infection has been described by numerous concordant studies published over the last thirty years and is now well established (level III).
Congenital CMV (cCMV) infection has a birth prevalence of 0.7% worldwide . However, birth prevalence varies according to the level of CMV immunity in pregnant women. The birth prevalence is the highest (>1%) in countries where maternal seroprevalence is high (>95%) such as most African and Asian countries. In countries with low maternal seroprevalence (around 50%) such as most European countries, the birth prevalence is the lowest around 0.4%. This reflects the burden of cCMV following maternal secondary infection. Indeed, fetal infection may follow maternal primary infection during pregnancy but also maternal secondary infection which happens in women already immune for CMV before pregnancy. The ratio between fetal infections related to maternal primary infections and those related to maternal secondary infections depends on the seroprevalence rate in pregnant women. In highly seroimmune populations, almost all fetal infections are related to secondary maternal infections . In countries with intermediate CMV seroprevalence (≈70%) such as the US, 25% of congenital infections are expected to be related to primary maternal infections and the other 75% to maternal secondary infections . In countries with low maternal seroprevalence such as most European countries (≈50%) an equal ratio between fetal infections related to primary infection and those related to maternal secondary infection is expected .
In a meta-analysis based on 15 studies with a total of 117,986 infants screened, the percentage of infected children with CMV-specific symptoms at birth was 12.7%, the percentage of symptomatic children with permanent sequelae was 40-58% and the percentage of children without symptoms at birth who developed permanent sequelae was estimated to be 13.5% . In most studies the definition of a symptomatic neonate is a neonate with clinical and/or laboratory abnormalities (petechia, microcephaly, hepatosplenomegaly, fetal growth restriction (FGR), chorioretinitis, thrombocytopenia, hepatitis and hearing loss). In older studies, hearing loss was not tested at birth and this criterion was not included in the definition of a symptomatic neonate. A first study reported that severe symptoms at birth and long-term sequelae were seen much more frequently among neonates infected after a maternal primary infection than in those infected after a secondary infection . However, the results of early first report have been challenged by more recent data from longitudinal studies published by the same group and by others, indicating that the fetal morbidity related to maternal secondary infection is in fact as high as that related to maternal primary infection. In a series of 300 neonates (176 infected after maternal primary infection and 124 after maternal secondary infection), the proportion of symptomatic neonates was 11% in both groups and the proportion of hearing loss was also 10% in both groups . In another long-term follow-up study, non-primary infections contributed substantially to the burden of childhood congenital CMV disease: half of the children presenting with moderate to severe outcomes were born from mothers with non-primary infections .
The epidemiology and pathophysiology of maternal secondary infections are not well understood.(level I) They could be related to either a reactivation of the endogen CMV strain or to a reinfection with a new CMV strain and the relative contribution of both mechanisms to the burden of secondary infection is unknown. The high genetic variability of the CMV genome with 4.7% variability between strains at nucleotide level could explain the possibility of re-infection . The likelihood of re-infection in pregnant women was suggested by the evidence of the acquisition of new CMV antibody specificities between serum samples collected before and after pregnancy in seropositive women who delivered an infected neonate . (level II).
Diagnosis of maternal infection
The diagnosis of primary CMV infection in pregnancy is ascertained when seroconversion is documented with the presence of CMV specific IgG in the serum of a pregnant women who was previously tested IgG negative in a serum, sample collected earlier in pregnancy. (level III) However, the opportunity to diagnose seroconversion is rarely feasible in the absence of screening and prospective monitoring.
In the absence of seroconversion and based on clinical experience, the recommended best practice for the diagnosis of CMV primary infection is to perform a serology test with measurement of both specific IgM and IgG . In very rare cases, IgM response may be transient with CMV-IgM antibodies persisting for a very short time and consequently undetected even in the context of a recent primary infection. However, in most primary infections IgM antibodies reach moderate to high levels and persist for weeks, so are unlikely to be missed by standard commercial kits. Therefore, the sensitivity of screening recent primary infections by IgM testing is very high. The main problem is to deal with the low specificity of IgM screening. There are numerous situations in which detection of CMV IgM is not related to a recent primary infection such as 1) persistent specific IgM that can be detect for months in some individuals, 2) IgM cross relativities related to other ongoing viral infection or to non-specific stimulation of the immune system, 3) rise in IgM levels in episodes of reactivation. The interpretation of a positive IgM test must therefore be cautious and the state of the art is to perform IgG avidity to discriminate between primary infection during or prior to the current pregnancy . CMV IgG avidity testing is now a proven, valuable laboratory tool for diagnosing primary CMV infection during pregnancy. This assay is based on the observation that CMV specific low avidity IgG are produced during the first months of infection whereas binding avidity of maternal IgG to CMV antigens increases over time and high avidity IgG are detected in remote infection. The avidity index expresses the percentage of IgG still bound to the CMV antigens following treatment with denaturing agents. In commercial avidity assays, avidity indices are classified in 3 categories according to their values: low avidity which is in favour of a recent primary infection within the last 3 months, high avidity which excludes the onset of a primary infection in the last 3 months or intermediate avidity which does not allow discrimination between recent or remote primary infection. Earlier studies reported a low concordance between avidity commercial assays whereas new generations of CMV avidity assays exhibit a better standardisation . In different studies evaluating transmission rates in relation to avidity results, around 30% of women with a low avidity value transmitted CMV to their offspring; in contrast, none of the women with high avidity during the first trimester transmitted CMV infection, and women with an intermediate-avidity result during the first trimester had a low risk of intrauterine transmission of around 5% . These findings have significant implications for prenatal counselling 1) women with high CMV IgG avidity during the first trimester can be assured that the risk of giving birth to an infected infant is low and invasive procedures to identify fetal infection are not needed, 2) whereas women with low avidity should be considered for further testing to assess fetal infection status. (level II).
One study reported that the presence of CMV DNA in maternal blood significantly increases the risk of viral transmission to the fetus in women with a primary infection , and viremia combined with avidity value allows calculation of the incremental risk of fetal transmission. Studies are needed to confirm these findings and to design an accurate model based on a combination of laboratory tests (IgG levels, IgM levels, IgG avidity and CMV PCR in maternal blood and urine) to predict which pregnancies would result in an infected fetus.
There are no validated laboratory serological or virological tools to diagnose maternal secondary infections.
Diagnosis of maternal infection
The diagnosis of primary CMV infection in pregnancy is ascertained when seroconversion is documented with the presence of CMV specific IgG in the serum of a pregnant women who was previously tested IgG negative in a serum, sample collected earlier in pregnancy. (level III) However, the opportunity to diagnose seroconversion is rarely feasible in the absence of screening and prospective monitoring.
In the absence of seroconversion and based on clinical experience, the recommended best practice for the diagnosis of CMV primary infection is to perform a serology test with measurement of both specific IgM and IgG . In very rare cases, IgM response may be transient with CMV-IgM antibodies persisting for a very short time and consequently undetected even in the context of a recent primary infection. However, in most primary infections IgM antibodies reach moderate to high levels and persist for weeks, so are unlikely to be missed by standard commercial kits. Therefore, the sensitivity of screening recent primary infections by IgM testing is very high. The main problem is to deal with the low specificity of IgM screening. There are numerous situations in which detection of CMV IgM is not related to a recent primary infection such as 1) persistent specific IgM that can be detect for months in some individuals, 2) IgM cross relativities related to other ongoing viral infection or to non-specific stimulation of the immune system, 3) rise in IgM levels in episodes of reactivation. The interpretation of a positive IgM test must therefore be cautious and the state of the art is to perform IgG avidity to discriminate between primary infection during or prior to the current pregnancy . CMV IgG avidity testing is now a proven, valuable laboratory tool for diagnosing primary CMV infection during pregnancy. This assay is based on the observation that CMV specific low avidity IgG are produced during the first months of infection whereas binding avidity of maternal IgG to CMV antigens increases over time and high avidity IgG are detected in remote infection. The avidity index expresses the percentage of IgG still bound to the CMV antigens following treatment with denaturing agents. In commercial avidity assays, avidity indices are classified in 3 categories according to their values: low avidity which is in favour of a recent primary infection within the last 3 months, high avidity which excludes the onset of a primary infection in the last 3 months or intermediate avidity which does not allow discrimination between recent or remote primary infection. Earlier studies reported a low concordance between avidity commercial assays whereas new generations of CMV avidity assays exhibit a better standardisation . In different studies evaluating transmission rates in relation to avidity results, around 30% of women with a low avidity value transmitted CMV to their offspring; in contrast, none of the women with high avidity during the first trimester transmitted CMV infection, and women with an intermediate-avidity result during the first trimester had a low risk of intrauterine transmission of around 5% . These findings have significant implications for prenatal counselling 1) women with high CMV IgG avidity during the first trimester can be assured that the risk of giving birth to an infected infant is low and invasive procedures to identify fetal infection are not needed, 2) whereas women with low avidity should be considered for further testing to assess fetal infection status. (level II).
One study reported that the presence of CMV DNA in maternal blood significantly increases the risk of viral transmission to the fetus in women with a primary infection , and viremia combined with avidity value allows calculation of the incremental risk of fetal transmission. Studies are needed to confirm these findings and to design an accurate model based on a combination of laboratory tests (IgG levels, IgM levels, IgG avidity and CMV PCR in maternal blood and urine) to predict which pregnancies would result in an infected fetus.
There are no validated laboratory serological or virological tools to diagnose maternal secondary infections.
Diagnosis of fetal infection
Both CMV primary infections in pregnancy and the presence of compatible ultrasound fetal signs are opportunities for diagnosis of CMV infection in the fetus.
From a series of studies published in the early 2000’s, detection of viral DNA by polymerase chain reaction (PCR) in the amniotic fluid has been recognized as the reference method for the diagnosis of fetal infection . (level III) Although virus isolation by culture in amniotic fluid has an absolute specificity it has a lower sensitivity than PCR and is no longer the reference method. Earlier studies based on traditional PCR method such as nested-PCR reported some false positive PCR results, challenging the specificity of CMV PCR in amniotic fluid. These false positive results are probably explained by laboratory contaminations which happened in those early days. Today the generalisation of automated real time PCR methods has helped to overcome the risk of contamination and achieve quasi-absolute specificity for prenatal diagnosis of CMV infection by PCR. The sensitivity of CMV PCR in amniotic fluid is also excellent when timing of amniocentesis is appropriate. Following maternal primary infection, the process leading to CMV excretion in the fetal urine will take an average of 6-8 weeks and this interval should be recognised in order to avoid false negative prenatal diagnosis . Amniocentesis should also be performed once fetal urination is well established and therefore not before 20 weeks.(level III) When the conditions of sampling are optimal, the sensitivity of prenatal diagnosis by PCR in amniotic fluid has been reported to be between 90 to 95%. These 5% to 10% of false negative prenatal diagnosis cases (neonates born infected following after a negative prenatal diagnosis) are explained by a late transplacental passage of the virus, later than 6 to 8 weeks after primary maternal infection. In a recent retrospective case control study, long-term outcomes at 2 years of age were compared between infants born after false amniocentesis (study group) and those with a positive amniocentesis (control group) . There were 0% (0/46) sequelae in the study group compared to 14% (13/91) in the control group. The reason for the good outcome in those cases with a false negative prenatal diagnosis could be: 1) the later transmission of the virus recognising that fetal infection at a later stage of pregnancy is likely to carry a better prognosis than fetal infection in the first trimester ( , 2) protection by an already mature maternal immunity that could be incapable of preventing fetal infection but capable of preventing fetal disease.
There have been concerns over the potential iatrogenic risk of CMV transmission during antenatal invasive procedures in the presence of viral DNA in maternal blood. However, two well-designed studies with significant sample size demonstrated that this risk was negligible. In these studies, the proportions of infected neonates were similar in mothers with negative CMV DNA detection in blood at the time of amniocentesis and in those with positive CMV DNA detection in blood at that time . Therefore, amniocentesis can safely be done in cases with concomitant positive DNA detection in the maternal blood. (level II).
Prognostic markers of fetal infection
Once the diagnosis of fetal infection is proven, the prognosis is established based on a combination of fetal imaging and fetal laboratory tests.
Imaging findings
( Table 1 ) The pathophysiology of fetal CMV infection leads one to expect progressive and sometimes only subtle or transient findings on ultrasound. CMV is a viraemic herpes virus that will reach the fetus via the umbical circulation. The placenta, where the virus replicates, will act as a barrier against CMV but also as a reservoir. Within 4 to 8 weeks following maternal viraemia, an early but inconstant sign of vertical transmission is therefore likely to be placentitis as defined by a thickness of 4 cm or more and a heterogeneous appearance typically with calcifications co-existing with hypoechoic areas.
| Severe US brain abnormalities | Mild US brain abnormalities | Extra-cerebral US abnormalities |
|---|---|---|
| Ventriculomegaly ∗ ≥ 15 mm | Mild ventriculomegaly ∗ (>10 to 15 mm) | ∗∗∗∗ Hyperechogenic bowel |
| Periventricular hyperechogenicity | Intra-ventricular adhesions | ∗∗∗ Hepatomegaly (right lobe ≥ 40 mm) |
| Hydrocephalus ∗∗ | Intracerebral calcifications | Splenomegaly (longest diameter ≥ 40 mm in the second trimester) |
| Microcephaly < -2DS | Subependymal cysts | Intra-uterine growth retardation (<5th centile) |
| Increased cisterna magna ≥ 8 mm | Choroid plexus cysts | Oligoamnios (deepest vertical pool < 2.5 cm) |
| Vermian hypoplasia | Calcifications of the lenticulostriate vessels in the basal ganglia | Polyhydramnios (deepest vertical pool > 10 cm) |
| Porencephaly | Ascites | |
| Lissencephaly | Pleural effusion | |
| Periventricular cystic lesions of the white matter | Fetal hydrops, subcutaneous oedema | |
| Agenesis of the corpus callosum | Placentomegaly ≥ 40 mm | |
| Intra-hepatitic calcifications |
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