Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 13, Number 11—November 2007
Dispatch

Primary versus Nonprimary Cytomegalovirus Infection during Pregnancy, Israel

Tables
Article Metrics
28
citations of this article
EID Journal Metrics on Scopus
Author affiliations: *Hadassah Medical Center–Hebrew University School of Medicine, Jerusalem, Israel; †Israel Ministry of Health, Jerusalem, Israel;

Cite 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 (13). 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 (47). Yet, several reports found increased vertical transmission after nonprimary CMV infection (49). 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 <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 fluid after gestational week 21 or 7 weeks after maternal symptoms (3,11), was applied for all amniocenteses. Amniotic fluid samples were inoculated onto MRC5 monolayers for CMV isolation (10), and DNA was amplified 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 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 110). 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). Clinical signs of CMV infection triggered 52 (25%) of the tests, while patient anxiety induced the rest. Clinical CMV symptoms were more common with primary than with nonprimary infections (53 [60.2%], and 44 [36.6%], respectively, p = 0.002).

Pregnancies with primary infection had significantly fewer live births than those with nonprimary infection (Table 1). Primary infections in the first 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).

The following analysis included 169 women (excluding 39 with miscarriages or ETOP before week 21). Of them, 100 had amniocentesis, with most in the nonprimary infection group 2, 62.7% (52/83), and the rest similarly distributed between nonprimary group 1, 42.9% (15/35), and primary infection, 40.7% (33/81). Approximately half of the amniocenteses provided evidence of fetal CMV infection, both in primary infection (16/33) and nonprimary infection group 1 (7/15), but only in 17.3% (9/52) of group 2 (p<0.001). Vertical transmission was determined from the amniotic fluid by culture (n = 12) or PCR (n = 30), abortus pathology (n = 6), or positive neonatal IgM (n = 2) or urine cultures (n = 13). Vertical transmission rates were 35.8% (24/76), 30.0% (9/30), and 15.3% (11/72) in the primary and nonprimary infection groups 1 and 2, respectively (p = 0.017). The relative risk for vertical transmission in primary infection was 1.83 (95% confidence interval 1.1–3.03, p = 0.019) versus nonprimary infection.

All liveborn babies had similar natal characteristics regardless of the maternal infection group. Four newborns and 7 aborted fetuses (6.5%, 11/169) had congenital CMV disease (Table 2), 6.0% (4/67) after primary CMV infection and 6.9% (7/102) after nonprimary infection, with 13.3% (4/30) in group 1 and 4.2% (3/72) in group 2 (p = 0.26). Three of the 4 mentally retarded neonates were born after nonprimary infection. CMV infection was not detected in newborns of mothers with negative prenatal diagnostic tests (n = 68).

Conclusions

To our knowledge, this is the first 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 (2,48,13). 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 findings 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% (13,13). 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 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 (48). 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.

Top

References

  1. Stagno  S, Pass  RF, Cloud  G, Britt  WJ, Henderson  RE, Walton  PD, Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. JAMA. 1986;256:19048. DOIPubMedGoogle Scholar
  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;326:6637.PubMedGoogle Scholar
  3. Revello  MG, Gerna  G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev. 2002;15:680715. DOIPubMedGoogle Scholar
  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;104:5560. DOIPubMedGoogle Scholar
  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;31:44357. DOIPubMedGoogle Scholar
  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;344:136671. DOIPubMedGoogle Scholar
  7. Ahlfors  K, Harris  S. Secondary maternal cytomegalovirus infection—a significant cause of congenital disease. Pediatrics. 2001;107:12278. DOIPubMedGoogle Scholar
  8. Daiminger  A, Bäder  U, Enders  G. Pre- and periconceptional primary cytomegalovirus infection: risk of vertical transmission and congenital disease. BJOG. 2005;112:16672. DOIPubMedGoogle Scholar
  9. Ross  SA, Fowler  KB, Ashrith  G, Stagno  S, Britt  WJ, Pass  RF, Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr. 2006;148:3326. DOIPubMedGoogle Scholar
  10. Lazzarotto  T, Varani  S, Gabrielli  L, Spezzacatena  P, Landini  MP. New advances in the diagnosis of congenital cytomegalovirus infection. Intervirology. 1999;42:3907. DOIPubMedGoogle Scholar
  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;95:8818. DOIPubMedGoogle Scholar
  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;94:90914. DOIPubMedGoogle Scholar
  13. Fowler  KB, Stagno  S, Pass  RF. Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA. 2003;289:100811. DOIPubMedGoogle Scholar
  14. Eddleman  KA, Malone  FD, Sullivan  L, Dukes  K, Berkowitz  RL, Kharbutli  Y, Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol. 2006;108:106772.PubMedGoogle Scholar

Top

Tables

Top

Cite This Article

DOI: 10.3201/eid1311.061289

1Current affiliation: Sheba Medical Center, Tel-Hashomer, Israel

Table of Contents – Volume 13, Number 11—November 2007

EID Search Options
presentation_01 Advanced Article Search – Search articles by author and/or keyword.
presentation_01 Articles by Country Search – Search articles by the topic country.
presentation_01 Article Type Search – Search articles by article type and issue.

Top

Comments

Please use the form below to submit correspondence to the authors or contact them at the following address:

Galia Rahav, Infectious Diseases, Sheba Medical Center, Tel-Hashomer 52621, Israel;

Send To

10000 character(s) remaining.

Top

Page created: July 04, 2010
Page updated: July 04, 2010
Page reviewed: July 04, 2010
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external