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Clinical and Diagnostic Laboratory Immunology, January 1999, p. 127-129, Vol. 6, No. 1
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Anticytomegalovirus (Anti-CMV) Immunoglobulin G
Avidity in Identification of Pregnant Women at Risk of Transmitting
Congenital CMV Infection
Tiziana
Lazzarotto,1
Patrizia
Spezzacatena,1
Stefania
Varani,1
Liliana
Gabrielli,1
Paola
Pradelli,1
Brunella
Guerra,2 and
Maria
Paola
Landini1,*
Department of Clinical and Experimental
Medicine, Section of Microbiology1 and
Second Department of Obstetrics and
Gynecology,2 Medical School, University of
Bologna, Bologna, Italy
Received 6 July 1998/Returned for modification 17 August
1998/Accepted 30 September 1998
 |
ABSTRACT |
In this work, we show that the determination of the
anticytomegalovirus antibody avidity carried out before week 18 of
gestation is a helpful tool to identify women for enrollment in
prenatal diagnosis. This procedure can identify all pregnant women who will give birth to an infected newborn.
| |
TEXT |
Congenital cytomegalovirus (CMV)
infection is the leading cause of congenital viral infection in
developed countries, occurring in approximately 1% of all live births
(1, 3, 4, 9, 18). Transmission of CMV to the fetus follows
approximately 40% of primary maternal infections, whereas
approximately 0.5% of women who are seropositive before pregnancy
deliver infected infants (17). In addition, symptomatic
infections and debilitating sequelae are rare in congenitally infected
children born to women with preexisting immunity to CMV (5).
Diagnosis of primary CMV infection in immunocompetent adults is
accomplished by serological methods (3). CMV-specific
immunoglobulin M (IgM) is a sensitive indicator of an ongoing or recent
infection. However, it is not a specific indicator of primary
infection, as it is often produced during nonprimary infections
(2, 10, 15). Another serological procedure useful in
identifying primary infections is the determination of IgG avidity
(6, 8, 11, 13).
In this work, we determined the avidity index (AI) of anti-CMV antibody
in 76 pregnant women at risk of transmitting CMV to their offspring as
well as in 20 pregnant women at no risk of transmitting CMV. All the
women went through prenatal diagnoses, and pregnancy outcomes were monitored.
Between January 1994 and May 1998, 76 pregnant women were enrolled in
the prenatal diagnosis program for CMV infection either because of a
seroconversion for CMV during the first trimester of pregnancy
(n = 15) or because of the presence of CMV-specific IgM
(n = 61).
Twenty pregnant women at no risk of fetal CMV transmission (as
determined by a negative IgM test) but who had amniotic fluid (AF) and
fetal blood taken for fetal karyotype assessment constituted a control
group. Twenty milliliters of AF was collected by amniocentesis at 21 to
23 weeks' gestation with informed consent from all women. CMV DNA was
individually extracted from 3 to 6 aliquots of AF (100 µl each), and
PCR was carried out as described in detail previously (12).
AF was considered positive if at least one of the aliquots was positive.
Congenital CMV infection in a newborn was determined by CMV isolation
(7) from urine or saliva during the first week of life.
The determination of IgG avidity was carried out using a commercial kit
(Cytomegalovirus IgG avidity EIA WELL; RADIM, Rome, Italy).
As shown in Table 1, we obtained blood
samples from 76 pregnant women during the early phase of pregnancy (6 to 18 weeks' gestation; mean, 13.6 weeks). Anti-CMV antibody avidity
was determined, and in only six cases it was not possible because of an
IgG level that was too low. Of these women, one with congenital
hypogammaglobulinemia who was found to be PCR positive in AF testing
decided to interrupt her pregnancy. No sign of CMV infection was found
in the fetus. The other five women continued their pregnancies, and no
congenitally infected newborn was documented. In the remaining 70 samples, the AI was determined, and the women were classified into one of the following three groups on the basis of the result obtained: low
AI (38 cases), moderate AI (6 cases), and high AI (26 cases). Of the 38 women who showed a low avidity, 17 had the viral genome in the AF
(45%) as detected by PCR. Thirteen women (seven who seroconverted and
six who were IgM positive) continued their pregnancies, and the virus
was isolated from six newborns (four asymptomatic and two symptomatic).
Four women (one who seroconverted and three who were IgM positive)
decided to interrupt their pregnancies, and all four fetuses showed the
presence of CMV in multiple organs (data not shown). A detailed
analysis of the results obtained on prenatal diagnoses has been
recently published (12).
View this table:
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|
TABLE 1.
Avidity index of anti-CMV IgG at two different gestation
times in relation to prenatal diagnosis carried out by PCR in amniotic
fluid and pregnancy outcomes in pregnant women at risk of transmitting
a CMV infection and in a control population
|
|
Among the six women with moderate avidity, two had the viral genome in
the AF (33%). All of them decided to continue their pregnancies, and
no congenital infection was documented in their newborns. Finally, of
26 women with high AI, 3 had the viral genome in the AF (11%). All of
them continued their pregnancies and no congenital infection was
documented in their newborns.
Later during pregnancy (at the time of amniocentesis, i.e., after 21 to
23 weeks' gestation), another blood sample was obtained from the same
76 pregnant women, and the AI was redetermined. As shown in the table,
the six samples with IgG levels too low to allow the determination of
AI at the first testing were again found to have low anti-CMV IgG
levels at the time of amniocentesis, and the AI could not be
determined. All six women had CMV-specific IgM, and one was excreting
the virus in urine. One of them suffered from congenital
hypogammaglobulinemia, and in four cases the presence of CMV-specific
IgM was not confirmed by blot, suggesting a false IgM positivity at the
first testing. No explanation for the observed delay in IgG development
for the other IgM-positive woman was found.
Of the 38 women who had anti-CMV antibody with low avidity at the first
testing, 32 (84%) still had a low AI at the time of amniocentesis. The
other six had reached either a moderate or a high avidity. Among the 32 women who still had a low AI at the time of amniocentesis, 6 (19%) had
a congenitally infected fetus or newborn. Among the 6 women with a
moderate avidity and the 32 with a high avidity at the time of
amniocentesis, one and three congenitally infected fetuses or newborns,
respectively, were documented.
We also determined the anti-CMV IgG avidity of 20 pregnant women who
had amniocentesis carried out due to genetic problems. The AI was
higher than 60% for all of them (data not shown). PCR carried out on
their AFs gave negative results, and no congenitally infected newborns
were found. From the data presented, we calculated the sensitivity and
specificity and the positive and negative predictive values of avidity
determination with regard to the outcome of pregnancy (Table 1).
The main finding of this article is that if the determination of the
anti-CMV antibody avidity is carried out early enough (before 18 weeks), it can identify all pregnant women who will transmit congenital
CMV infection to their offspring. Furthermore, if the determination of
AI is carried out later on during pregnancy, 60% of the women who will
transmit the infection still have antibody with low avidity, while the
others have developed a moderate or high avidity.
Interestingly, PCR detected viral DNA in the AF of 17 of
76 women, and in only 10 of the samples did we document a
congenital infection in fetuses or newborns. This is probably
due to the high sensitivity of the procedure, which detects a viral
load so low as to be cleared by the fetal defenses, and is
consistent with other published data (14, 16). Quantitative
PCR is in progress to verify this hypothesis.
In conclusion, the early determination of anti-CMV antibody avidity is
a helpful tool to identify a subgroup of IgM-positive women to enroll
in prenatal diagnosis.
| |
ACKNOWLEDGMENTS |
This work was partially supported by Istituto Superiore di
Sanità, Progetto, Sicurezza del Sangue e dei suoi Prodotti (1996) and the AIDS projects (1997 and 1998) and by the Italian Ministry of
Education (40 and 60%).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Dipartimento di
Medicina Clinica Specialistica e Sperimentale, Sezione di
Microbiologia, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna,
Italy. Phone: 39.051.341652. Fax: 39.051.341632. E-mail:
viroland{at}med.unibo.it.
| |
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Clinical and Diagnostic Laboratory Immunology, January 1999, p. 127-129, Vol. 6, No. 1
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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