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ORIGINAL RESEARCH |
From the Laboratory of Virology, Departments of Obstetrics and Gynecology, Hôpital Universitaire Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Address reprint requests to: Corinne Liesnard, MD Laboratory of Virology Hopital Erasme 808 Route de Lennik Brussels B-1070 Belgium E-mail: cliesnar{at}ulb.ac.be
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Abstract |
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Methods: We studied 237 pregnant women who had suspected or confirmed primary CMV infections by amniocenteses with or without funipuncture. Diagnosis of CMV was based on culture and polymerase chain reaction (PCR) done on amniotic fluid (AF) samples; fetal blood tests for CMV immunoglobulin M antibodies, PCR, and nonspecific biologic markers; and repeated ultrasound examinations. In cases of pregnancy termination, viral and pathologic examinations of fetuses were done. At birth, CMV infections were sought in newborns. Pediatric follow-up was scheduled for at least 2 years.
Results: Of 210 fetuses and newborns correctly evaluated, 55 had CMV infections. Ten of 38 fetuses infected before 20 weeks’ pregnancy had severe congenital disease. The global sensitivity of prenatal diagnosis was 80%. Best sensitivity and 100% specificity were achieved by PCR done on AF sampled after 21 weeks’ gestation, respecting a mean interval of 7 weeks between diagnosis of maternal infection and prenatal diagnosis. Fetal thrombocytopenia was associated with severe fetal disease. Ultrasound follow-up missed two fetuses who presented with neurologic impairment due to CMV after birth.
Conclusion: A reliable prenatal diagnosis of congenital CMV infection based on PCR on amniocentesis samples can be made after 21 weeks’ pregnancy, after a 7-week interval between diagnosis of maternal infection and antenatal procedure. Ultrasound and nonspecific biologic parameters are not sufficient to identify all fetuses at risk of severe sequelae.
With an incidence of 0.2–2.2% of live births, cytomegalovirus (CMV) infection is the most frequent congenital infection worldwide.1 It is a common cause of deafness and intellectual function impairment.2,3 Ninety percent of congenitally infected infants are asymptomatic at birth, but 5%–17% of them develop symptoms, usually during the first 2 years of life. Among the 10% of symptomatic newborns, 20% will die and 90% of the survivors will develop severe sequelae.4 After primary infection during pregnancy, the rate of transmission to the fetus ranges between 15% and 75% (mean 40%).4 Congenital CMV infections in children of women who have CMV antibodies before conception are less likely to be symptomatic at birth or present with later sequelae,3 although a recent study found symptomatic infections at birth in infants born to immune women.5 Primary infections in the first half of pregnancy appear to have the worst outcomes,6,7 even in some severe cases when transmission occured later in pregnancy.8,9 Prenatal diagnosis of congenital CMV infection has been reported in several studies10–19 by ultrasonography, amniocentesis, and fetal blood sampling in limited series. The purpose of our study was to investigate the accuracy of prenatal diagnosis in a prospective series of 239 fetuses at risk of congenital CMV infection, and to evaluate possible prognostic markers in infected fetuses.
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Materials and Methods |
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After written informed consent was obtained, prenatal diagnosis was made by amniocentesis, funipuncture, and repeated ultrasound examinations. One amniocentesis was done in every case and at least one funipuncture was done in 218 cases. Among 348 amniocenteses, 239 funipunctures were done. Amniocentesis alone was done in 18 women (19 fetuses). In 119 cases, funipuncture was done simultaneously with amniocentesis. In all other cases a second sampling of amniotic fluid (AF) or of AF and fetal blood was done, and in some cases a third sample was collected. Amniotic fluid samples were inoculated into shell vials and MRC5 monolayers for CMV isolation.
Cytomegalovirus DNA amplification was done by polymerase chain reaction (PCR) on all AF samples.14 In 1992, we introduced nested PCR on the major immediate early gene of CMV into our methods. The first 32 AF samples were investigated by simple PCR and subsequent cases with nested PCR. At least four aliquots of 5 µL of AF were assayed in two different PCR runs. In the last 157 cases, we added a second nested PCR on the CMV pp150 gene to eventually amplified CMV strains with major immediate-early sequence variations that could have been missed by major immediate-early–nested PCR. To exclude PCR inhibitors in AF with negative PCR and culture results in proven infected cases, we retrospectively spiked them with a 1:100 dilution of positive CMV culture and retested them by PCR.
Fetal blood sampling was done after 21 weeks’ pregnancy as previously reported.23 Cytomegalovirus IgM antibodies were sought in 232 fetal blood samples, corresponding with 209 cases; nested PCR was done in 196 fetal blood samples, corresponding with 177 cases; and CMV culture was done in 99 fetal blood samples, corresponding with 83 cases. Nonspecific tests included hemoglobin count and hematocrit, platelet count, and measurements of 
-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase.
To investigate the possibility of transmitting the virus through diagnostic procedure, we looked for CMV antigenemia in maternal blood using the method of Gerna et al24 in 75 recent cases, and we investigated the presence of CMV DNA in 84 maternal blood samples by nested PCR. Those tests were done on blood specimens taken at the moment of first antenatal diagnostic procedure. Periods (weeks) between maternal infection and antenatal diagnosis procedure were calculated starting from the date of the first positive maternal serology result.
The decision to continue or terminate pregnancy was made after discussions among the parents, the gynecologist, and our group. When termination of pregnancy was chosen, pathologic studies and viral cultures were done on placental and fetal tissues. In some cases, viral and pathologic studies were incomplete or not available. At birth, urine and saliva samples were cultured for CMV as described, and a neonate blood sample was analyzed for the same markers as fetal blood. Congenital CMV infection was considered certain when it was detected in at least one urine or saliva sample collected during the first week of life. Newborns not investigated by urine or saliva cultures, but who had positive CMV IgM antibody detection, also were considered congenitally infected. In congenitally infected neonates, CMV IgM antibody detection by enzyme-linked immunosorbant assay tests has a sensitivity of 50–80%, but non-specific results are infrequently reported20,25 and CMV IgM antibodies in newborns is presumptive or even a criterion of congenital CMV infection.8,26 Cerebral ultrasounds, ophthalmologic examinations, and hearing evaluations were done in most of the infants and systematically when CMV infection was diagnosed. Pediatric follow-up was scheduled for at least 2 years. Information on infants was collected by regular questionnaires sent to pediatricians, and phone contacts.
We calculated 95% confidence intervals (CIs) and proportion comparisons were done using Pearson 
2 tests or Fisher exact test when normal approximation was not valid. Computations were done with SPSS software (SPSS 8.0; SPSS Inc., Chicago, IL) and with StatXact software version 3 (Cytel Software Corp., Cambridge, MA). Power analysis was calculated for a 10% effect size using nQuery Advisor version 2.0 (Statistical Solutions Ltd., Cork, Ireland). Periods were compared using nonparametric Mann–Whitney test.
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Results |
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Fifty-five fetuses and newborns (24%) had evidence of CMV infections at abortion or birth. Table 1
shows the distribution of women and infected fetuses in each group. In the primary infection group, the rate of fetal infection was not statistically different between subgroups (P = .75, power 93%). In the CMV IgM–positive subgroup, no more than 8 weeks’ gestation, subgroup no transmission was observed, which is strikingly different compared with the primary infection, no more than 8 weeks subgroup (P = .004) and to the other IgM subgroups in which the transmission rates were not different from the primary infection group (P = .715, power 98%).
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Considering the first AF of cases sampled before 21 weeks’ gestation, the sensitivity was only 30% (six of 20). In 35 cases investigated for the first time after 21 weeks’ pregnancy, 26 (74%) were diagnosed, 25 by AF (71%) and 17 of 28 by fetal blood (61%). The difference in sensitivity between amniocentesis before and after 21 weeks’ gestation was statistically significant (P = .005). In all undiagnosed infected pregnancies except one, only one prenatal sample was collected. In 24 infected pregnancies with multiple samplings at different moments during pregnancy, antenatal diagnosis was positive in 23 (96%). In 16 of those cases, the first sampling was done before 21 weeks’ pregnancy and was negative in 12. Among the 44 diagnosed infected pregnancies, 12 were diagnosed at the second sampling. In 12 cases with positive antenatal diagnoses, results in later samples always confirmed the diagnosis. Twenty of 27 negative AF samples in 25 infected cases were still available. The artificially introduced virus could be amplified in all, showing that inhibitors of PCR were not major causes of negative results in infected cases.
Comparison of the periods between serologic diagnosis of mothers and negative antenatal results or positive antenatal results on the first antenatal sampling in infected cases is shown in Table 2. Positive antenatal diagnosis was made after a mean time lapse of 6.6 weeks.
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. Diagnoses of congenital CMV infection were made in 19 cases. In seven fetuses, virologic and pathologic investigations at termination of pregnancy were not done. Four of those cases were reported elsewhere.14 In those seven fetuses, the conjunction of central nervous system (CNS) anomalies, culture and PCR detection of the virus in the AF and in the placenta, and CMV IgM in the fetal blood established diagnoses of CMV infection. Eight cases had ultrasonographic abnormalities during pregnancy. Except for two hydrocephalic fetuses and one microcephalic fetus not investigated, ultrasonographic anomalies were seen in fetuses with disseminated infection (CMV detected in at least two organs). However, at least 12 fetuses with disseminated infections at autopsy had no ultrasonographic anomalies at termination of pregnancy. In nine cases, fetal blood platelets were significantly diminished. At least six of those fetuses presented with disseminated infection, hydrocephaly, or severe fetal growth restriction.
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details the results of neonatal diagnostic tests and outcomes at follow-up of the 29 infected newborns. There were ultrasound anomalies in six of those pregnancies, only one of which had gyration delay associated with microcephaly and developed a severe neurologic handicap. In that case, first positive serology result of the mother was detected during the ninth week of gestation, suggesting that the infection was very early in her pregnancy. Three infants without ultrasonographic anomalies during gestation developed complications. In one diamniotic, dichorionic heterozygote twin pregnancy, one twin was infected and asymptomatic at birth, and later developed a heavy neurologic handicap, and the other was free of infection. Six cases had elevated -glutamyl transferase in fetal blood, that disappeared at birth or soon after. Seven infected infants of 22 tested had CMV IgM antibodies at birth. One hundred fifty-three newborns were confirmed free of CMV infections by negative cultures of urine and saliva samples collected within the first 2 weeks of life. Four of them had mild thrombocytopenia and three had moderately elevated -glutamyl transferase in their blood at cordocentesis. Combining aborted fetuses with severe ultrasonographic anomalies as CNS involvement and severe FGR and infected newborns with poor outcomes (Tables 3
and 4), CMV disease seemed to be more severe when maternal infection occurred before 20 weeks’ gestation: among 38 fetuses, ten (26%) had severe CMV disease and sequelae. Among 16 cases infected after 20 weeks’ gestation, only one had a minor sequela of retinitis. One infected newborn of the subgroup of women with CMV IgG and IgM antibodies at first serologic investigation detected after 20 weeks’ gestation had severe neurologic sequelae. Maternal diagnosis was made during the third trimester, but by definition previous serologic investigations were not done, so the infection could have been earlier in pregnancy.
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Discussion |
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We found a global sensitivity of prenatal diagnosis of 80%. Most series of CMV antenatal diagnoses reported 20–50% false negative results.14–16,19 Lipitz et al17 detected all infected fetuses at amniocentesis, but half those cases were referred because of ultrasonographic anomalies associated with CMV IgM antibodies in the mothers, indicating that the infections were already in the fetus at the moment of antenatal diagnostic sampling. All antenatal diagnoses were made after 21 weeks’ pregnancy, and in a subgroup of symptomatic women, after a mean interval of 7 weeks between maternal symptoms and amniocentesis. In our study, absence of PCR inhibitors in negative AF of infected cases and positive results on second samplings suggested that negative results are obtained when antenatal diagnosis is done too close to maternal infection (mean 4.5 weeks). Determining the right time for antenatal diagnostic procedure remains difficult, and was also encountered in antenatal diagnosis of congenital toxoplasmosis, in which 10–20% of infected cases were missed by antenatal diagnosis based on PCR and mouse inoculation of AF, probably because at amniocentesis the parasite was not yet in the fetus.27,28 French authors recommended an interval of at least 4 weeks between the serologic diagnosis of maternal CMV infection and amniocentesis, which according to them should be done after 18 weeks’ pregnancy.16 Applying those recommendations to our series, we would have obtained at least 23% of false-negative antenatal diagnoses among eligible cases. According to our experience, antenatal diagnosis should be after 21 weeks’ pregnancy, respecting a lapse of at least 7 (6.6) weeks after the first positive maternal serology test for good sensitivity.
We found PCR on AF to be the most sensitive test to diagnose congenital infection. Our sensitivity of culture compared with PCR was 84%. Other studies found no difference in sensitivity between culture and PCR,16,17,19 which is surprising because many reports on PCR for detecting CMV in other clinical fields found higher sensitivity of PCR compared with culture.24,29,30 We used a nested PCR instead of single-round PCR and tested multiple aliquots of AF. Revello et al31 improved sensitivity of their nested PCR by increasing the quantity of AF extracted, as we did. Using quantitative PCR, they found low levels of CMV DNA in the AF of three of 21 infected fetuses that could not be detected by culture,32 which suggests that sensitivity of PCR on AF could depend on the quantity of AF explored and the intrinsic sensitivity of the PCR protocol.
The risk of CMV transmission during diagnostic procedures is reasonably excluded. At diagnostic procedure, no maternal CMV antigenemia was detected, and detection of CMV DNA by PCR in maternal blood was infrequent, indicating that active CMV infection during antenatal diagnostic procedures was probably rare. We did not find different transmission rates between women with one antenatal sampling and women with multiple samplings. If transmission through antenatal diagnostic procedure had happened, we would have observed a higher transmission rate than in retrospective studies without antenatal intervention.
We showed 100% specificity of PCR and culture in detection of CMV in AF. When the virus was detected by culture or PCR in the AF, it was systematically recovered from fetal tissues or excreted by newborns in all investigated cases. Thus, the virus in the AF is a marker of fetal and congenital infection. High specificity of antenatal diagnosis was found in other series, too14–17,19 except in the study of Lazzarotto et al.18 They suggested that the high sensitivity of PCR detected small quantities of virus later eliminated by the fetus. Contaminations in PCR work or insensitivity of the culture method used to detect infected newborns could also explain those results.
Our study confirms previous observations6,7 that severe fetal CMV disease seems to be associated with maternal infection in the first part of pregnancy. However, because pregnancies without severe ultrasound signs were also terminated, it is difficult to estimate what would have been the prognosis of those fetuses. If fetuses with multiorgan CMV involvement are considered potentially severely affected after birth, in our series the risk of a severe congenital CMV disease would have been 43%, a percentage largely superior to series without antenatal intervention,3,6 suggesting that part of disseminated infections in fetuses can heal in utero without important sequelae, as described in one case report.33 In a twin pregnancy in our series, one twin was infected and later developed sequelae and the other one was free of infection. In other case reports of twin or multiple pregnancies, one or more infants were severely affected and the remaining twins had asymptomatic infections.34–36 All the observations support the idea that, apart from maternal CMV immune response, placental and fetal factors also affect intrauterine transmission and development of fetal disease.
In our study, nonspecific tests used as possible prognostic markers of fetal disease were not very contributive. Although fetal thrombocytopenia was seen in fetuses with signs of severe disease, the marker was missing in other severely diseased fetuses. Fetal thrombocytopenia also can be transient.14 The prognostic value of other fetal blood parameters could be more promising. In a small series, Revello et al37 investigated quantitative fetal blood levels of CMV antigen, virus, and DNA and found an association between high levels of CMV and symptomatic infection. The value of funipuncture must be balanced against the risk because in our series one noninfected fetus died in utero after funipuncture.
A routine serologic screening of women of childbearing age would ideally determine their immune status toward CMV before pregnancy to avoid interpretation problems of CMV IgM–positive results. However, no woman in our study with CMV IgM antibodies detected in the first 8 weeks’ pregnancy without IgG evolution transmitted infection to her fetus. Determination of IgG avidity also could help diagnose past infections.38,39 Even without preconceptional serology testing, serologic identification of women at risk of primary infection remains possible in early pregnancy. Seronegative pregnant women should be counseled about risks of CMV transmission and preventive precautions. In the case of seroconversion, we believe that safe and reliable prenatal diagnosis based on PCR of amniocentesis samples could be proposed. We could not identify a sensitive prognostic parameter in fetal blood, and careful ultrasound follow-up did not detect all fetuses at risk for neurologic defects. Evaluation of the performances of quantitative markers of CMV infection in antenatal samples and cranial magnetic resonance in infected fetuses would be of great interest for improving the prognostic significance of antenatal diagnosis; however, antenatal diagnosis can provide clear information useful for clinical decisions on termination of pregnancy, early monitoring of infected newborns for birth complications, and scheduling pediatric follow-up for later sequelae. A pilot study and a phase II study showed some efficacy of ganciclovir for congenital CMV infection.40,41 More studies on antiviral therapy in congenitally infected infants are needed to determine the potential benefits of drugs such as ganciclovir, oral ganciclovir, foscarnet, and new anti-CMV compounds. Prenatal therapy with nontoxic antiviral drugs or Igs should be considered and studied.
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Footnotes |
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Received August 16, 1999. Received in revised form November 22, 1999. Accepted December 9, 1999.
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