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ORIGINAL RESEARCH |
From the Department of Gynecology and Obstetrics, the Division of Neonatology, and the Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Address reprint requests to: Patrick Hohlfeld, MD, Service d’Obstetrique, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland, E-mail: patrick.hohlfeld{at}chuv.hospvd.ch
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Abstract |
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Methods: One hundred ten pregnant women (four with twin pregnancies) with a risk of congenital CMV infection were investigated. Prenatal diagnosis was carried out by amniocentesis and fetal blood sampling (n = 75) or amniocentesis alone (n = 35). Serial ultrasonographic examinations were performed from time of referral until pregnancy end. All infected neonates were given long-term follow-up. Autopsy was performed in all cases of termination of pregnancy.
Results: Nearly 23% (26 of 114) of fetuses were infected and prenatal diagnosis was positive in 20 cases. Sensitivity of prenatal diagnosis was 77% and specificity 100%. In eight cases, parents requested termination of pregnancy on the basis of abnormal ultrasonographic findings and/or biologic abnormalities in fetal blood. In 12 cases, parents decided to proceed with the pregnancy. In this group, one intrauterine and one neonatal death were observed. In one case, prenatal diagnosis revealed an abnormal cerebral sonography and the infant had bilateral hearing loss at birth. In 15 cases (nine positive and six false-negative prenatal diagnoses), no apparent lesion was present at birth, nor did it develop during the follow-up period (mean 31 months). In 88 (77.2%) of 114 infants, no evidence of vertical transmission was found during the pre- or postnatal period.
Conclusion: Prenatal diagnosis provides the optimal means for both diagnosing fetal infection (amniocentesis) and identifying fetuses at risk of severe sequelae (ultrasound examination, fetal blood sampling), thus allowing proper counseling.
Human cytomegalovirus (CMV) is the most common cause of viral intrauterine infection, affecting 0.5–2.5% of all live births in different parts of the world.1–3 The incidence of congenital CMV infection is high because mothers can transmit the virus to their fetuses following either primary or recurrent infection.1,2,4,5
The prevalence of CMV infection varies according to socioeconomic background. In the United States the seropositivity rate is 50–60% for women of middle-class background, but it is 70–80% for those from lower socioeconomic sectors.4,6 In Europe, 45% (range 43–73%) of pregnant women are seropositive at the beginning of pregnancy.7–10
The risk of seroconversion during pregnancy averages 2.0–2.5%, ranging from 0.47% to 12.9%.2,4,6–11 The rate of congenital infection resulting from primary maternal infection is about 30%, ranging from 15% to 50%,2–4,12,13 and after a recurrent infection (reactivation or reinfection) it is 0.15–1%.2,4
Ten percent of congenitally infected infants have congenital CMV syndrome, whereas 90% are asymptomatic at birth2,3,6; however, 10–15% of the latter are at risk of developing a multitude of developmental abnormalities such as sensorineural hearing loss, chorioretinitis, or neurologic deficits.6 Among the most severely affected infants, mortality may be as high as 30%.2 More than 90% of the infants surviving CMV disease have late complications, such as hearing loss, mental retardation, delay in psychomotor development, chorioretinitis, optic atrophy, seizures, expressive language delays, and learning disabilities.2
Gestational age has no influence on the risk of intrauterine transmission. However, the clinical consequence for the infected offspring appears to be worse when infection takes place before 20 weeks’ gestation.2,4,6
It is well established that isolation of the virus in the amniotic fluid (AF) is the most reliable index of congenital infection.3,9,14–18 As experience with prenatal diagnosis of congenital CMV infection remains limited, we report here the results obtained prospectively in 110 pregnancies at risk of congenital CMV infection.
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Materials and Methods |
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The women were divided into four groups. Group A included 51 patients with documented maternal seroconversion during pregnancy. Group B included 33 patients with documented maternal seroconversion in the periconception period. Group C comprised 16 patients with possible seroconversion during pregnancy in which it was impossible to differentiate with certainty a primary from a recurrent infection or to determine the exact timing of the infection (anti-CMV immunoglobulin [Ig] M antibodies can be detected in primary and recurrent infections and the immune status of these women was not known before pregnancy). Group D comprised ten patients referred because of abnormal second- or third-trimester ultrasonographic findings.
Serologic diagnosis of primary CMV infection was documented by seroconversion (ie, the appearance of de novo specific IgG and IgM antibodies in a patient who had been seronegative) or a significant rise of IgG antibody titer in the presence of specific IgM antibodies associated with low IgG avidity. A CMV-specific IgG avidity test can differentiate primary from nonprimary infection.13,19,20 In the case of high avidity, the infection is either nonprimary or took place more than 12 weeks earlier.19
The following assays were used for the serologic diagnosis: standard complement fixation test, enzyme-linked fluorescent assay for anti-CMV IgG, and µ-antibody capture enzyme-linked immunosorbent assay (ELISA) for the determination of specific IgM. Avidity of IgG antibodies was measured by means of a commercial ELISA (ELISA, Dade Behring, Deerfield, IL) using a modified procedure.20 All maternal IgG and IgM tests were checked in our laboratory. The interval between the two maternal IgG titers was 2–4 weeks.
Two methods of prenatal diagnosis were used in 75 subjects, involving a combination of amniocentesis and fetal blood sampling under ultrasound guidance as described by Daffos et al.21 Thirty-five patients underwent amniocentesis only. Amniotic fluid and fetal blood samples were immediately forwarded to the laboratory for the detection of early viral antigen fluorescent foci22 and for conventional cell cultures. The purity of fetal blood was confirmed in all cases as described by Forestier et al.23 Indirect signs of fetal infection included abnormalities in full blood count (anemia, thrombocytopenia), elevated liver function tests, and increased total IgM concentration. Specific IgM antibody determination in fetal blood was performed by two different ELISAs.
A detailed ultrasonographic examination took place every 4 weeks from the time of referral until the end of pregnancy. In the case of positive AF cultures, ultrasonographic examinations were more frequent (bimonthly).
When pregnancy termination was elected, pathologic studies and fetal tissue viral cultures were used to confirm the diagnosis.
At birth, virus isolation from the neonate’s urine was performed systematically. A blood sample was tested to detect specific anti-CMV IgM. In all cases of congenital CMV infection, cerebral ultrasound, auditory-evoked potentials, and fundoscopy were performed systematically. All infected neonates were included in a regular long-term follow-up program to detect hearing loss or developmental impairments. For all congenitally infected infants, complete follow-up information was obtained from their pediatricians. For uninfected infants, information was gathered from either the pediatrician or the parents in all cases but one (lost to follow-up).
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Results |
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Prenatal diagnosis (by positive viral isolation in the AF) allowed the demonstration of CMV infection in 20 of 114 fetuses. All diagnoses of fetal infection were obtained within 24 hours by using the early viral antigen detection in AF and were confirmed by culture. Fetal blood sampling was performed in all cases of demonstrated fetal infection: specific anti-CMV IgM was detected in 15 of 20 fetuses and fetal blood culture was positive in six (Table 1
). No case of positive fetal blood culture or fetal blood-specific IgM with negative AF culture was recorded. No complications were observed after fetal blood sampling or amniocentesis. In this series, there was no false-positive result. All congenital infections were confirmed by the isolation of CMV in urine samples collected within the first days of life. This procedure enabled us to detect six additional cases of congenital infection (false-negative prenatal diagnoses).
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Abnormal ultrasonographic findings were observed in five (19.2%) of 26 infected fetuses. Following fetal blood sampling, abnormal hematologic and/or liver function tests were demonstrated in nine (45%) of 20 fetuses.
The pregnancy outcomes in the cases with congenital infection are presented in Table 1
. With positive prenatal diagnosis, eight of 20 parents requested termination of pregnancy, motivated by abnormal ultrasonographic findings and/or biologic abnormalities demonstrated by fetal blood sampling. Table 2 summarizes the results of different prenatal and postmortem examinations in these cases. On postmortem examination, CMV was isolated from various organs (brain, liver, lungs, kidneys, thyroid, adrenals, and placenta) in seven of eight fetuses (cultures not performed in one case).
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Case 1 was a twin pregnancy referred at 28 weeks, because of massive nonimmune hydrops in one fetus. Amniocentesis was positive in the hydropic fetus and fetal blood showed numerous indirect signs of infection (severe anemia [27 g/L], thrombocytopenia [15 x 199/L], and abnormal liver function tests). The other fetus underwent the same prenatal tests, but was found uninfected. Following premature rupture of membranes at 33 weeks, the patient underwent cesarean delivery. She gave birth to a healthy boy, whereas the infected co-twin died soon after birth. Prenatal diagnosis was confirmed by typical CMV disease in the first twin and absence of infection in the second.
Despite positive congenital infection and abnormal cerebral ultrasound (periventricular calcifications), one patient (case 4) continued her pregnancy and at 38 weeks delivered a girl, in whom severe bilateral hearing loss was detected at birth. Since the age of 8 months the infant has had hearing aids for both ears and she began speech therapy at an early age. Her degree of deafness has remained stable. Despite the auditory deficiency, the child has no psychomotor abnormalities or mental retardation. She is currently well integrated in a normal school program, with additional specialized classes for children with hearing deficiencies.
Fifteen pregnancies (nine diagnosed infected fetuses and six false-negative fetuses) ended with the delivery of infants having no apparent disease at birth or during a median follow-up period of 31.2 months (range 5–76 months).
In 88 (77.2%) of 114 infants, no evidence of vertical transmission was found. The median follow-up period for these uninfected infants was 47.6 months (range 6–112 months) and uncovered no abnormalities.
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Discussion |
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The overall rate of vertical transmission was 22.8%, but the rate was higher for documented primary maternal infection (41%). No case of positive fetal blood-specific IgM or fetal blood culture with negative AF culture was recorded. Nor was any complication observed after fetal blood sampling or amniocentesis.
In our series, 20 of the 26 congenital infections were detected by prenatal diagnosis on the basis of AF culture alone. All positive diagnoses were obtained within 24 hours by using the early viral antigen detection. This finding confirms that amniocentesis is the most reliable means to detect congenital infection.3,9,14–18
Sensitivity for anti-CMV IgM antibody detection in fetal blood reached 75% and fetal blood culture was positive in 30%; therefore, the information yielded by fetal blood sampling did not add to the accuracy of the diagnosis of vertical transmission.
Prenatal diagnosis was false negative in six cases. The mothers of all six neonates had documented primary CMV infection during pregnancy and amniocentesis was performed 6–14 weeks later. The infants were all asymptomatic at birth and none of them developed any abnormality during a median follow-up period of 21.3 months (range 5–61 months). Because all laboratory tests were performed immediately after sampling, it seems unlikely that the false-negative results were due to delay in transport or in processing the samples. It has been recommended that prenatal diagnosis be performed after 21 weeks,10,17 but failing to do so cannot explain all false-negative cases, because two of the six were sampled at 23 and 26 weeks. The time lapse between maternal infection and prenatal diagnosis should be a minimum of 6 weeks.17,24 Considering that this delay was respected in all false-negative cases, and that in one case the interval was 14 weeks, we hypothesized that a recurrence of maternal infection during pregnancy could be responsible for a later fetal infection. However, as suggested by others,10,18,24 low viral load could account for false-negative results and perhaps for less severe infections.
The most difficult step in the prenatal diagnosis of fetal CMV infection is to estimate the prognosis. Detection of the virus in the AF, presence of IgM in fetal blood, or positive fetal blood culture are all evidence of fetal infection. However, these findings have no prognostic value concerning the development of serious disease or severe sequelae and termination of pregnancy should not be considered on this basis. The presence of systemic CMV infection in the fetus is not universally associated with a severely handicapped neonate.25 However, intrauterine resolution of hematologic and hepatic disturbances is, in fact, a marker for a better outcome.25
Although fetal blood sampling and ultrasonography may be helpful in assessing the fetal condition,14,15,18,25 prediction of outcome will be difficult if based on ultrasonographic findings alone.26 At the beginning of our experience, all patients underwent amniocentesis and fetal blood sampling. Presently, we consider only fetal blood sampling when fetal infection has been demonstrated in AF studies.
After careful, long-term monitoring (average 31.2 months) of congenitally infected infants to assess the prognostic significance and diagnostic reliability of the prenatal diagnosis, we think that these results should be taken into account when discussing the pros and cons of obstetric screening for CMV. Screening together with prenatal diagnosis could be considered for the following reasons: women who are seropositive before conception do not need to be tested serologically or virologically, nor do they need to worry unduly about transmitting the virus to their fetus. Although a few cases of symptomatic congenital CMV infection after recurrent maternal infection have been reported,1,7,27,28 fetal damage is a result of primary maternal infection in the vast majority of cases.2 It is well recognized that maternal immunity before conception provides substantial protection against severe congenital CMV infection in the newborn.1,6,27,29 On the other hand, women who are seronegative, and therefore susceptible to primary infection, may benefit from preventive measures (eg, a behavioral prevention approach to reduce child-to-adult transmission of CMV).30
In case of maternal primary infection during pregnancy, amniocentesis, a reliable method for the diagnosis of fetal infection, can be carried out easily, and the result can be obtained within 24 hours. Moreover, about 60% of pregnant women with primary infection show no evidence of vertical transmission. Analysis of fetal blood could be helpful in estimating the prognosis of a known fetal infection when severe anemia or thrombocytopenia is present. Prenatal diagnosis of congenital infection allows the close observation of congenitally infected infants in the first years of life. Such follow-up of these cases will, in turn, mean rapid detection and correction of hearing loss, reducing the risk of secondary developmental disorders. At present, there is no approved intrauterine treatment for CMV congenital infection. Should a safe and effective therapy be developed, prenatal diagnosis would become a routine part of obstetric care whenever maternal CMV infection occurs. Pregnancies with evidence of vertical transmission and definite ultrasonographic findings such as microcephaly, hydrocephaly, and intracranial calcifications are at significant risk of severe sequelae. In our experience, fetal CMV infection—in the absence of cerebral lesions or severe biologic abnormalities—has been associated with a good prognosis.
To minimize the disease burden resulting from CMV congenital infection, the use of a vaccine seems the only logical approach. In view of the complexities involved in the development of a safe and protective vaccine, we believe that the prenatal diagnosis described above provides the optimal means for not only diagnosing fetal CMV infection, but also for defining pregnancies without a significant risk of severe sequelae and thus guiding the patient as to whether her pregnancy can be continued with a high level of confidence.
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Footnotes |
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Received May 1, 2000. Received in revised form July 25, 2000. Accepted August 17, 2000.
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References |
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2. Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, et al. Primary cytomegalovirus infection in pregnancy: Incidence, transmission to fetus, and clinical outcome. JAMA 1986;256: 1904–8.[Abstract]
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