Primary versus Nonprimary Cytomegalovirus Infection during Pregnancy, Israel

We examined prospectively the outcome of primary and nonprimary maternal cytomegalovirus (CMV) infection during pregnancy among 88 and 120 women, respectively. The risk for vertical transmission was 1.83× higher for primary infection than for nonprimary infection. Nonetheless, congenital CMV disease was diagnosed in both infection groups at similar rates.

We examined prospectively the outcome of primary and nonprimary maternal cytomegalovirus (CMV) infection during pregnancy among 88 and 120 women, respectively. The risk for vertical transmission was 1.83× higher for primary infection than for nonprimary infection. Nonetheless, congenital CMV disease was diagnosed in both infection groups at similar rates.

C ytomegalovirus (CMV) infection is the most frequent
congenital infection and a common cause of deafness and intellectual impairment, affecting 0.5%-2.5% of all live births (1)(2)(3). Intrauterine infection occurs in 40% of primary maternal infections, with delivery of 10% to 15% symptomatic newborns and late neurologic sequelae in 10% of those asymptomatic at birth (1).

The Study
Institutional Ethics Committee approval was obtained. Women with positive CMV immunoglobulin (Ig) M (n = 208), referred for risk for CMV infection between January 1998 and December 2001, were enrolled in this prospective cohort observational study. Clinical and pregnancy-related information was obtained. Serum CMV IgG and IgM were measured by enzyme immunoassay and CMV-IgM immunofl uorescence assay (10). IgG avidities <25% indicated recent infection (10).
Ultrasonographic examinations were performed between the 15th and 21st weeks of pregnancy. The reference method for prenatal diagnosis of CMV, requiring combined viral isolation and positive CMV PCR from amniotic fl uid after gestational week 21 or 7 weeks after maternal symptoms (3,11), was applied for all amniocenteses. Amniotic fl uid samples were inoculated onto MRC5 monolayers for CMV isolation (10), and DNA was amplifi ed by PCR (10,12). Parents made decisions regarding amniocentesis and the fate of pregnancy after medical, and sometimes rabbinical, consultations. Elective terminations of pregnancy (ETOP) required external committee approval. Available aborted fetuses were examined for CMV-induced histopathologic changes. Immediately after birth, neonatal urine and anti-CMV IgM were examined. Subsequently, the newborns underwent cerebral ultrasound and auditory and ophthalmologic assessment.
Primary infection was defi ned as the occurrence of anti-CMV IgG seroconversion during pregnancy (1). Women who were seropositive for anti-CMV IgM and anti-CMV IgG when fi rst evaluated during pregnancy and with IgG avidity >35% were considered to have nonprimary infection (12). The latter were divided into those with preconception evidence of anti-CMV IgG and negative anti-CMV IgM (group 1) and those without prior tests for CMV (group 2). Vertical transmission was declared if the amniotic fl uid contained CMV virus or DNA, if pathologic features of CMV disease existed in the aborted fetus, or if neonatal IgM or urine cultures were positive for CMV.
Analysis of variance and the Kruskal-Wallis or Mann-Whitney tests were used. Frequencies were compared by χ 2 or Fisher exact tests. Relative risk was calculated with Epi Info 2000 software (available from www.cdc.gov/epiinfo).
Pregnancies with primary infection had signifi cantly fewer live births than those with nonprimary infection (Table 1). Primary infections in the fi rst 20 gestational weeks resulted in 46.5% live births, 46.5% ETOP, and 7% miscarriages, while pregnancies with such infections after week 23 were 100% full term (p = 0.004).

Conclusions
To our knowledge, this is the fi rst cohort in which the natural history of nonprimary CMV infection was evaluated prospectively in the mother from pregnancy to its conclusion, in contrast to published studies that determined it from established neonatal infection and retrospective assessment of the mothers' serologic test results (2,(4)(5)(6)(7)(8)13). Most Israeli physicians obtain CMV serologic test results in pregnancy in response to women's demands and as a precaution, but the results, mainly of nonprimary infection, are confusing. Our fi ndings suggest that nonprimary infection is also dangerous. While vertical transmission after primary CMV infection was similar to the reported 30% to 40% (1,3,11), after nonprimary infection it was 19.6%, much higher than the published 2.2% (1)(2)(3)13). Furthermore, of the 11 cases of congenital CMV disease, 7 were associated with nonprimary maternal infection.
The high rate of vertical transmission in the nonprimary infection group attests to the numerous amniocenteses performed in Israel to exclude fetal infection. The procedure is considered safe because neonatal loss rates in those undergoing it and not undergoing it are identical (14), and the risks of undergoing the procedure do not outweigh the risks for congenital CMV infection. In the nonprimary group, 67 (55.8%) had amniocentesis, but in the primary infection group, only 33 (37.5%) underwent the procedure, which refl ects the increased early ETOP rate with primary infection.
Traditionally, vertical transmission after nonprimary infection was established by isolating CMV from neonatal saliva or urine, or the presence of neonatal IgM (4-8). We, however, determined transmission also from CMV in the amniotic fl uid, and the observed difference between amniotic CMV and neonatal CMV disease suggests fetal virus elimination between amniocentesis and birth, probably by preexisting maternal CMV-specifi c antibodies. The high transmission rate could have resulted also from reinfection by CMV strains different from the primary strain (6), further enhanced by increased virulence of present-day strains.
The high proportion (>40%) of religiously observant women accounts for the reluctance of some to terminate pregnancy without ultrasonographic and amniocentesis evidence of fetal infection and also for the increased early ETOP (permitted by Jewish law only before the second trimester). We are aware that data were obtained for only 169/199 (84.9%) of fetuses or newborns and that only 31/51 (60.8%) of the aborted fetuses were available for examination, but omissions were random. Possible referral selection bias and the low number of affected women discourage defi nitive conclusions. Nevertheless, both primary and nonprimary CMV infection during pregnancy are clearly important causes of congenital disease. Dr Rahav is the director of the Infectious Diseases Unit, Sheba Medical Center, Tel-Hashomer, Israel. Her research interests include mycobacterial infections, bacterial strain typing, HIV-1 reverse transcriptase, and congenital CMV infection.