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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 1.83x higher for primary infection than for nonprimary infection. Nonetheless, congenital CMV disease was diagnosed in both infection groups at similar rates.

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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 [less than or equal to] 25% indicated recent infection (10).

Ultrasonographic examinations were performed between the 15th and 21 st 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--ME 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 [chi square] 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). 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 (2,4-8,13). 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 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% (1-3,13). 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 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.

The opinions expressed by authors contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention or the institutions with which the authors are affiliated.

References

(1.) Stagno S, Pass RF, Cloud G, Britt W J, 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, Bader 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 MR New advances in the diagnosis of congenital cytomegalovirns 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.

Address for correspondence: Galia Rahav, Infectious Diseases, Sheba Medical Center, Tel-Hashomer 52621, Israel; email: galia.rahav@sheba. health.gov.il

Galia Rahav, *(1) Rinat Gabbay, * Asher Ornoy, *([dagger]) Svetlana Shechtman, ([dagger]) Judith Arnon,([dagger]) and Orna Diav-Citrin ([dagger])

* Hadassah Medical Center--Hebrew University School of Medicine, Jerusalem, Israel; and ([dagger]) Israel Ministry of Health, Jerusalem, Israel

(1) Current affiliation: Sheba Medical Center, Tel-Hashomer, Israel
Table 1. Outcome of pregnancies by type of CMV infection *

Outcome of pregnancy Primary Nonprimary
 infection (%) infection (%)

Live birth 51 (58.0) 97 (80.8)
ETOP * 30 (34.0) 21 (17.5)
Miscarriage ([dagger]) 7 (8.0) 2 (1.7)
Total 88 120

Outcome of pregnancy Total p value

Live birth 148 <0.001
ETOP * 51 0.006
Miscarriage ([dagger]) 9 0.038
Total 208

* CMV, cytomegalovirus; ETOP, elective termination of pregnancy.
Thirty ETOP were performed during the first trimester, 21 between
the 21st and 23rd weeks of pregnancy.

([dagger]) Mean gestational age of miscarried fetuses was 7 wk.

Table 2. Characteristics of aborted fetuses and neonates with
congenital CMV disease *

 Maternal Maternal Week of
Case no. infection symptoms infection US AF

1 Primary Flu <20 IUGR +
 microcephaly

2 Primary None <18 Hyperechoic ND
 bowel

3 Primary Fever 7 Hyperechoic +
 bowel

4 Primary Fever 12 None +

5 Nonprimary None Unclear IUGR ND
 (group 1)

6 Nonprimary Flu 22 Tricuspid ND
 (group 1) regurgitation

7 Nonprimary Fever 20 IUGR +
 (group 1) pericardial
 fluid, brain
 calcifications

8 Nonprimary Flu <20 None +
 (group 1)

9 Nonprimary Fever 12 ND +
 (group 2)

10 Nonprimary Flu 4 ND ND
 (group 2)

11 Nonprimary None 14 Liver +
 (group 2) calcifications

 Natal/abortion
Case no. Outcome, wk status Follow-up, 2 y

1 Live born, 38 Congenital Sensorineural
 disease hearing loss,
 PMR

2 Abortion, 19 Postmortem:
 disseminated
 CMV

3 Abortion, 23 Postmortem:
 disseminated
 CMV

4 Abortion, 24 Postmortem:
 disseminated
 CMV

5 Live born, 38 Brain PMR
 calcifications

6 Abortion, 33 Postmortem:
 disseminated
 CMV

7 Abortion, 30 Postmortem:
 disseminated
 CMV

8 Live born, 40 Congenital PMR
 disease

9 Abortion, 24 Postmortem:
 disseminated
 CMV

10 Live born, 38 Congenital Sensorineural
 disease hearing loss,
 PMR

11 Abortion, 24 Postmortem:
 disseminated
 CMV

* CMV, cytomegalovirus; US, ultrasonography; AF, amniotic fluid; IUGR,
intrauterine growth retardation; +, positive according to PCR,
culture, or both; ND, not done; PMR, psychomotor retardation.
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Author:Rahav, Galia; Gabbay, Rinat; Ornoy, Asher; Shechtman, Svetlana; Arnon, Judith; Diav-Citrin, Orna
Publication:Emerging Infectious Diseases
Date:Nov 1, 2007
Words:2201
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