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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Chaim Sheba Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
Address reprint requests to: Shlomo Lipitz, MD, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, 52621, Israel; E-mail: slipitz{at}hotmail.co.il.
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ABSTRACT |
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METHODS: We recruited 50 pregnant women (51 fetuses) with primary cytomegalovirus infection and confirmed in utero transmission. Prenatal evaluation included diagnostic amniocentesis and repeated ultrasound examinations. Fetal diagnosis was made after 21 weeks’ gestation by amniocentesis and based on virus isolation by culture, shell vial, and polymerase chain reaction (PCR). Cytomegalovirus infection in neonates was determined by urinary viral isolation after birth or histologic examination of tissue from aborted fetuses. Cerebral ultrasound, hearing assessment, and psychomotor development were investigated for all 18 live-born neonates.
RESULTS: Thirty-three of the 50 women (66%) elected termination of pregnancy. Ultrasonographic abnormalities associated with in utero fetal infection were observed in 11 (21.5%) fetuses. Two of them continued to term; both were congenitally infected, and one had neurologic abnormalities. The positive predictive values of the PCR and virus isolation assessments performed in all 50 pregnancies (51 gestational sacs) were 92% and 93.7%, respectively. Seventeen pregnancies (18 fetuses) continued to term: four fetuses had neurologic abnormalities, of which three had normal prenatal ultrasound findings. The remaining 14 had normal neonatal assessments.
CONCLUSION: Positive isolation of cytomegalovirus accompanied by positive PCR values in amniotic fluid provided approximately 94% certainty of in utero cytomegalovirus infection. The risk of postnatal neurologic abnormalities was 19% (three of 16) when there were no prenatal ultrasonographic abnormalities.
Cytomegalovirus infection is the most frequent congenital infection worldwide, with an incidence of 0.2–2.2% of live births.1,2 Ten percent of congenitally infected infants are symptomatic at birth: 20% of them will die and 90% of the survivors will develop long-term sequelae, such as hearing impairment or neurologic abnormalities.3 In addition, 5–17% of asymptomatic newborns will develop symptoms, usually during the first 2 years of life.3–5 Given that congenital cytomegalovirus infection is relatively a common cause of hearing loss and mental retardation,3,6 its antenatal diagnosis and prevention is a major challenge in perinatology.
After primary infection during pregnancy, the rate of transmission to the fetus is approximately 40%.6 Children of women who have cytomegalovirus antibodies before conception are partially protected and have only a 0.5–1% risk of congenital infection as well as lower risk of later sequelae.4,7,8 Although recurrent infections occasionally occur with different cytomegalovirus strains,9 recent studies have estimated that at least 45–52% of all congenitally infected infants are born to preconceptionally immune women.9,10
Primary infections in the first half of pregnancy appear to have the worst outcomes.11,12 Recent advances in cytomegalovirus serology have refined the workup of pregnant women at risk of primary or recurrent cytomegalovirus infection.13 Contemporary prenatal diagnosis and management of in utero cytomegalovirus infection include ultrasonography, amniocentesis for antigenicity, viral culture, polymerase chain reaction (PCR), and rarely fetal blood sampling.14–16 The major limitation of these techniques is that positive results of amniotic fluid tests, such as viral isolation and PCR, do not discriminate between the infants who will have symptoms at birth and those who will not,17,18 although quantitative PCR might partially enable such a prediction.19,20
Most women with maternal cytomegalovirus infection who consent to diagnostic amniocentesis elect to terminate the pregnancy when vertical transmission is confirmed. Thus, the information on the neonatal outcomes of pregnancies with proven maternal infection and vertical transmission is sparse.
In 1997, we reported the results of the prenatal evaluation of 63 pregnant women with primary cytomegalovirus infection and the neonatal outcomes of six infants with documented vertical transmission born to the women who elected to continue the pregnancy.14 The aim of the present study was to document our experience with 50 pregnancies (51 fetuses) with cytomegalovirus infection that all have confirmed intrauterine cytomegalovirus infection, 17 of which (18 fetuses) continued to term.
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MATERIALS AND METHODS |
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The study design was prospective, with neonatal follow-up being a strict requirement, as was documentation of transplacental cytomegalovirus. The inclination of the women to terminate their pregnancy in which transplacental transmission of cytomegalovirus was confirmed led to a relatively small study group.
Screening for prenatal cytomegalovirus infection is not mandatory in Israel but is performed according to the physician’s decision and the woman’s consent. Most of the women included in the present study (n = 44) were evaluated as part of a routine random screening program, and detailed sonography was performed near the time of positive cytomegalovirus serology. The other six women were evaluated because of sonographic findings indicative of possible abnormalities. Information on the precise timing of maternal infection was available for few of the study participants, but most of the women were known to have been infected during the first half of the pregnancy.
Each study subject had cytomegalovirus infection documented by the presence of cytomegalovirus-specific immunoglobulin (Ig) G or IgM (or both) in recent serologic assays. Maternal IgG or IgM assays were performed in various laboratories using enzyme-linked immunosorbent assay. Maternal primary infection was defined by the presence of cytomegalovirus-specific IgG or IgM (or both) in previously seronegative women or when there was a significant increase (according to the standards of each laboratory) in IgG titer (within an interval of 3–4 weeks) in the presence of IgM antibodies. When needed, anticytomegalovirus-IgG avidity testing was done to distinguish between primary and recurrent or nonrecent infection.
After written informed consent was obtained, the prenatal diagnosis was made by amniocentesis and repeated detailed ultrasonographic examination (every 3–4 weeks) to identify any abnormality associated with in utero fetal infection. Amniocentesis was performed in all cases after 21 weeks’ gestation and at least 6 weeks after the first positive serology results. Transabdominal ultrasound-guided amniocentesis was performed using a 20-gauge needle to collect 30 mL of amniotic fluid for the cytomegalovirus assays and for karyotyping.
Each fetal diagnosis was made after using three different methods to diagnose cytomegalovirus infection in amniotic fluid. Cytomegalovirus isolation was performed by culture on fibroblasts, by the shell vial technique,21,22 and by PCR amplification of cytomegalovirus DNA on amniotic fluid samples as previously described.23 Only cases with a positive PCR or virus isolation were evaluated and are presented here. After such evidence became available, the couples then consulted a specialist in fetal medicine. Thirty-three women elected to terminate their pregnancies, whereas 17 women (18 fetuses) decided to continue them. Their demographic data are presented in Table 1
. In cases of termination, the abortuses were examined for histopathologic evidence of cytomegalovirus infection, but the complete anatomicopathologic findings were not recorded.
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Statistical analysis was performed using the SPSS for Windows 9.0 (SPSS Inc, Chicago, IL). Estimated predictive measures were provided with 90% confidence intervals (CI).
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RESULTS |
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The antenatal test results and the presence or absence of congenital infection at birth are summarized in Table 2. The PCR finding was positive in all singleton pregnancies and in one of the two sacs of the twin pregnancy (50 of 51 gestational sacs), and 92% (46 of 50) of fetuses had congenital infection. Shell vial and cytomegalovirus culture yielded the same results in all cases and were positive in 48 of 51 gestational sacs (94.1%); 93.7% (45 of 48) had congenital infection. Two singleton pregnancies that only had positive PCR continued to term, and only one had congenital cytomegalovirus infection.
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Abnormal ultrasonographic findings were recorded in 11 (21.5%) of 51 fetuses with evidence of vertical transmission (Table 3). Nine of these 11 women (82%) with abnormal fetal ultrasonographic findings elected to terminate the pregnancy. Each abortus was examined and found to have cytomegalovirus infection. Seventeen women (18 fetuses, including two with abnormal ultrasonographic findings) elected to continue their pregnancies with follow-up. Thirteen of these pregnancies (76%) resulted in fourteen infants who had no apparent disease throughout the neonatal course, within a median follow-up period of 32 months (range 6–96 months). The two cases with abnormal ultrasonographic findings that continued to term were both congenitally infected and one had neurologic abnormalities.
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). No prenatal abnormal ultrasonographic findings had been recorded in three of them. Accordingly, the risk of postnatal neurologic abnormalities was 19% (three of 16) when there were no prenatal ultrasonographic findings. The fourth neonate, who had prenatal evidence of growth restriction and ventriculomegaly, has cerebral palsy and is deaf.
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DISCUSSION |
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Viral isolation methods assist antenatal evaluation by reducing the false-positive rate of PCR. Based on our results and previous reports,24 PCR-positive qualitative results predict congenital infection with a probability of 91–98%.16,17,24 We observed similar high positive predictive values (92–94%) when PCR or culture was used to detect cytomegalovirus in amniotic fluid. We did, however, find some discrepancy between antenatal investigation and postnatal diagnosis.
Small amounts of viral DNA in the absence of viral isolation have been reported in amniotic fluid.18 Revello et al20 recently reported that approximately 33% of fetuses with a positive PCR result and negative virus isolation had no congenital cytomegalovirus infection. Thus, the virus might have been eliminated in utero. The present study included two such cases with a positive PCR finding and negative cytomegalovirus isolation. Only one of them did not have congenital infection.
Perhaps more interesting are the three cases that had both positive PCR results and viral isolation but no congenital infection. This raises the question of whether fetal cytomegalovirus infection is sometimes self-limited in utero, even when the virus had been isolated from the amniotic fluid. It is well accepted, however, that cytomegalovirus isolation from amniotic fluid is of limited value to clinicians when counseling couples on the risk of symptomatic infection. In contrast, it was recently reported that a quantitative PCR count of 103 genome equivalents per mL of amniotic fluid was a certain sign of congenital infection and that 105 genome equivalents per mL can predict symptomatic infection.25 This guideline may greatly influence the couple’s decision whether to terminate the pregnancy.
When quantitative PCR is not available, prenatal consultation in cases of documented vertical cytomegalovirus infection consists of risk assessment according to amniotic fluid studies and detailed ultrasonographic evaluations. When ultrasonographic abnormalities associated with in utero fetal infection are identified, it might increase the risk of adverse neonatal outcomes, as our results show, although all these fetuses had congenital infection. Our results showed that the risk of postnatal neurologic abnormalities was 19% when there were no prenatal ultrasonographic findings, and no valid conclusions can be drawn from the two cases with ultrasonographic abnormalities in which the pregnancies were brought to term.
The severity of the sonographic abnormalities probably plays an important role in prognosis. The significance of mild signs of fetal infection, eg, hyperechogenic bowel, in the presence of maternal infection is still unknown.26 One such case in our study group had a normal outcome after follow-up of 22 months. In another series of 135 newborns with antenatal hyperechogenic bowel, two had cytomegalovirus infection: these two newborns, however, also had cerebral calcifications that were probably missed in the prenatal sonography.27 In a recent prospective analysis of 60 fetuses with isolated hyperechogenic bowel,28 no cases of congenital cytomegalovirus infection were reported.
The only case with serious sonographic abnormalities (ventriculomegaly) that continued to term had a grim outcome. The prenatal ultrasonographic findings of the other three live-born neonates with neonatal abnormalities were normal. The significance of this issue calls for the retrieval of more data in larger series in order to provide more information that can be used in the consultation of women with documented vertical transmission of cytomegalovirus infection.
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Footnotes |
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Received October 12, 2001. Received in revised form March 19, 2002. Accepted April 4, 2002.
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REFERENCES |
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