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*Hadassah Medical Center–Hebrew University School of Medicine, Jerusalem, Israel; and †Israel Ministry of Health, Jerusalem, Israel
Volume 13, Number 11–November 2007
Suggested citation for this article
Abstract
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.
Cytomegalovirus (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 (1–3). 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).
Although preexisting maternal immunity reduces maternal-fetal transmission, the severity of congenital CMV disease is similar following primary or nonprimary infection (4–7). Yet, several reports found increased vertical transmission after nonprimary CMV infection (4–9). Therefore, our objective was to examine the outcome of primary and nonprimary maternal CMV infections during pregnancy.
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 immunofluorescence assay (10). IgG avidities .
PRIMARY INFECTION was defined as the occurrence of anti–CMV IgG seroconversion during pregnancy (1). Women who were seropositive for anti–CMV IgM and anti–CMV IgG when first 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 fluid 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 χ2 or Fisher exact tests. Relative risk was calculated with Epi Info 2000 software (available from www.cdc.gov/epiinfo).
Of the 208 enrolled women, 88 (42.3%) had primary CMV infection; 120 (57.7%) had nonprimary CMV infection, 36 (17.3%) from group 1 and 84 (40.4%) from group 2. The mothers' ages were similar in both groups. The median gestational age upon referral was 15 weeks (9.5–19.0 weeks), and the median number of pregnancies was 3 (range 1–10). CMV serologic testing was part of the routine gynecologic examination in 127 (61.0%) of the women: 35 (39.8%) after primary infection and 92 (76.6%) in the nonprimary infection group (p<0.001). p =" 0.002)." p =" 0.004)." n =" 12)" n =" 30)," n =" 6)," n =" 2)" n =" 13)." p =" 0.017)." p =" 0.019)" p =" 0.26)." n ="">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 reflects 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 fluid, and the observed difference between amniotic CMV and neonatal CMV disease suggests fetal virus elimination between amniocentesis and birth, probably by preexisting maternal CMV-specific 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 definitive 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.
References
1. 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.
2. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med. 1992;326:663–7.
3. Revello MG, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev. 2002;15:680–715.
4. Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics. 1999;104:55–60.
5. Ahlfors K, Ivarsson SA, Harris S. Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature. Scand J Infect Dis. 1999;31:443–57.
6. Boppana SB, Rivera LB, Fowler KB, Mach M, Britt WJ. Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med. 2001;344:1366–71.
7. Ahlfors K, Harris S. Secondary maternal cytomegalovirus infection—a significant cause of congenital disease. Pediatrics. 2001;107:1227–8.
8. Daiminger A, Bäder U, Enders G. Pre- and periconceptional primary cytomegalovirus infection: risk of vertical transmission and congenital disease. BJOG. 2005;112:166–72.
9. Ross SA, Fowler KB, Ashrith G, Stagno S, Britt WJ, Pass RF, et al. Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr. 2006;148:332–6.
10. Lazzarotto T, Varani S, Gabrielli L, Spezzacatena P, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. Intervirology. 1999;42:390–7.
11. Liesnard C, Donner C, Brancart F, Gosselin F, Delforge ML, Rodesch F. Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Obstet Gynecol. 2000;95:881–8.
12. Nigro G, Mazzocco M, Anceschi MM, La Torre R, Antonelli G, Cosmi EV. Prenatal diagnosis of fetal cytomegalovirus infection following primary or recurrent maternal infection. Obstet Gynecol. 1999;94:909–14.
13. Fowler KB, Stagno S, Pass RF. Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA. 2003;289:1008–11.
14. Eddleman KA, Malone FD, Sullivan L, Dukes K, Berkowitz RL, Kharbutli Y, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol. 2006;108:1067–72.
Tables
Table 1. Outcome of pregnancies by type of CMV infection
Table 2. Characteristics of aborted fetuses and neonates with congenital CMV disease
Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, U.S.A
Tel: (404) 639-3311 / Public Inquiries: (404) 639-3534 / (800) 311-3435
Analysis of variance and the Kruskal-Wallis or Mann-Whitney tests were used. Frequencies were compared by χ2 or Fisher exact tests. Relative risk was calculated with Epi Info 2000 software (available from www.cdc.gov/epiinfo).
Of the 208 enrolled women, 88 (42.3%) had primary CMV infection; 120 (57.7%) had nonprimary CMV infection, 36 (17.3%) from group 1 and 84 (40.4%) from group 2. The mothers' ages were similar in both groups. The median gestational age upon referral was 15 weeks (9.5–19.0 weeks), and the median number of pregnancies was 3 (range 1–10). CMV serologic testing was part of the routine gynecologic examination in 127 (61.0%) of the women: 35 (39.8%) after primary infection and 92 (76.6%) in the nonprimary infection group (p<0.001). p =" 0.002)." p =" 0.004)." n =" 12)" n =" 30)," n =" 6)," n =" 2)" n =" 13)." p =" 0.017)." p =" 0.019)" p =" 0.26)." n ="">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 reflects 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 fluid, and the observed difference between amniotic CMV and neonatal CMV disease suggests fetal virus elimination between amniocentesis and birth, probably by preexisting maternal CMV-specific 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 definitive 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.
References
1. 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.
2. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med. 1992;326:663–7.
3. Revello MG, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev. 2002;15:680–715.
4. Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics. 1999;104:55–60.
5. Ahlfors K, Ivarsson SA, Harris S. Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature. Scand J Infect Dis. 1999;31:443–57.
6. Boppana SB, Rivera LB, Fowler KB, Mach M, Britt WJ. Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med. 2001;344:1366–71.
7. Ahlfors K, Harris S. Secondary maternal cytomegalovirus infection—a significant cause of congenital disease. Pediatrics. 2001;107:1227–8.
8. Daiminger A, Bäder U, Enders G. Pre- and periconceptional primary cytomegalovirus infection: risk of vertical transmission and congenital disease. BJOG. 2005;112:166–72.
9. Ross SA, Fowler KB, Ashrith G, Stagno S, Britt WJ, Pass RF, et al. Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr. 2006;148:332–6.
10. Lazzarotto T, Varani S, Gabrielli L, Spezzacatena P, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. Intervirology. 1999;42:390–7.
11. Liesnard C, Donner C, Brancart F, Gosselin F, Delforge ML, Rodesch F. Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Obstet Gynecol. 2000;95:881–8.
12. Nigro G, Mazzocco M, Anceschi MM, La Torre R, Antonelli G, Cosmi EV. Prenatal diagnosis of fetal cytomegalovirus infection following primary or recurrent maternal infection. Obstet Gynecol. 1999;94:909–14.
13. Fowler KB, Stagno S, Pass RF. Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA. 2003;289:1008–11.
14. Eddleman KA, Malone FD, Sullivan L, Dukes K, Berkowitz RL, Kharbutli Y, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol. 2006;108:1067–72.
Tables
Table 1. Outcome of pregnancies by type of CMV infection
Table 2. Characteristics of aborted fetuses and neonates with congenital CMV disease
Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, U.S.A
Tel: (404) 639-3311 / Public Inquiries: (404) 639-3534 / (800) 311-3435
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