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Brief Report |

Maternal Immunity and Prevention of Congenital Cytomegalovirus Infection FREE

Karen B. Fowler, DrPH; Sergio Stagno, MD; Robert F. Pass, MD
[+] Author Affiliations

Author Affiliations: Departments of Pediatrics (Drs Fowler, Stagno, and Pass), Epidemiology (Dr Fowler), Maternal and Child Health (Dr Fowler), and Microbiology (Drs Stagno and Pass), University of Alabama, Birmingham.


JAMA. 2003;289(8):1008-1011. doi:10.1001/jama.289.8.1008.
Text Size: A A A
Published online

Context Vaccine development to prevent congenital cytomegalovirus (CMV) infection has been impeded by the uncertainty over whether maternal immunity protects the fetus.

Objective To determine whether the presence of maternal antibodies to CMV significantly reduces the risk of congenital CMV infection in future pregnancies.

Design, Setting, and Participants Cohort study of 3461 multiparous women from a population with a high rate of congenital CMV infection who delivered newborns screened for congenital CMV infection between 1993 and 1998, and whose cord serum specimen from a previous delivery could be retrieved and tested for antibody to CMV.

Main Outcome Measure Congenital CMV infection according to maternal immune status, age, race, parity, and socioeconomic status.

Results Of 604 newborns born to initially seronegative mothers, congenital CMV infection occurred in 18 (3.0%). In contrast, of 2857 newborns born to immune mothers, congenital CMV infection occurred in 29 (1.0%) Two factors, preconception maternal immunity (adjusted risk ratio, 0.31; 95% confidence interval, 0.17-0.58) and maternal age of 25 years or older (adjusted risk ratio, 0.19; 95% confidence interval, 0.07-0.49), were highly protective against congenital CMV infection. No other factors were associated with a reduction in the risk of congenital CMV infection.

Conclusion Naturally acquired immunity results in a 69% reduction in the risk of congenital CMV infection in future pregnancies.

Figures in this Article

Congenital cytomegalovirus (CMV) infection remains a major public health problem in the United States because of its frequency and its role as a cause of sensorineural hearing loss, cognitive impairment, cerebral palsy, and visual impairment.1,2 Congenital CMV infection is a leading cause of sensorineural hearing loss in children and the leading infectious cause of central nervous system damage in children in the United States.24 Development of a vaccine for prevention of congenital CMV infection was listed as a top priority by the Institute of Medicine of the National Academy of Sciences in an analysis of cost of disease and impact on quality-adjusted life-years.5

Virus can be transmitted to the fetus during primary maternal infection during pregnancy, but it also can be transmitted even when maternal infection occurred years prior to conception.6 Whether maternal immunity decreases the frequency of transplacental transmission of CMV has not been previously studied. Uncertainty over the ability of naturally acquired immunity to prevent future infection is a major impediment to development of vaccines for prevention of congenital CMV infection. To test the hypothesis that preconception maternal immunity reduces the risk of congenital CMV infection, we compared rates of congenital infection according to maternal CMV serological status determined years prior to delivery.

Study Population

Women who delivered a newborn at the university hospital in the southern part of the United States between January 1993 and December 1998 were included in the study population if the following criteria were met: (1) the newborn was screened for congenital CMV infection; (2) the mother had 1 or more previous live births at the university hospital; (3) a cord serum specimen from a previous delivery could be retrieved and tested for IgG antibody to CMV. Cord serum specimens were stored at −20°C in a repository. The study was approved by the institutional review board at the University of Alabama, Birmingham. Written informed consent was obtained from the mothers of infants with congenital CMV infection who attended follow-up clinics. The institutional review board waived consent for those without CMV infection.

Between 1993 and 1998, 7558 multiparous women delivered at the university hospital (Figure 1). Of these women, 4132 had a prior delivery at the university hospital, and 3461 had available cord serum specimens. The latter group comprises the study population. The 671 women who delivered between January 1993 and December 1998 and had a previous delivery at the university hospital but did not meet study criteria because a cord serum specimen was not available did not differ from the study population in either race or insurance status. However, these excluded women were slightly younger.

Figure. Construction of the Cohort of Multiparous Women
Graphic Jump Location
CMV indicates cytomegalovirus.
Serological and Virological Tests

The CMV-specific IgG antibodies were measured using a commercially available enzyme immunoassay (ImX, Abbott Laboratories, North Chicago, Ill). Seroconversion was determined by simultaneously measuring the presence of CMV IgG antibodies in the cord serum specimen of the current delivery and the absence of CMV IgG antibodies in the cord serum specimen from the previous delivery in women who were initially CMV seronegative.7 Newborns were screened for congenital CMV infection by detection of virus in saliva using a rapid culture method.8 All CMV-positive results on a newborn screening test were confirmed by the isolation of the virus from urine and/or saliva at a 3- or 4-week postnatal follow-up clinic visit. Between 1993 and 1998, newborns delivered at the university hospital were routinely screened for congenital CMV infection with 88% screened during this time.

Statistical Analysis

Characteristics of the study population by maternal antibody status were compared using χ2 tests or t tests when appropriate. Rates were measured for independent and dependent variables. The 95% confidence intervals (CIs) were calculated by exact binomial methods. Risk ratios (RRs) were calculated from 2 × 2 tables and 95% CIs were calculated from exact binomial methods. Multivariate unconditional logistic regression using backward stepwise selection at a significance level of .05 was used to assess whether putative risk factors might modify the association between preconception antibody status and risk of congenital CMV infection. All data analyses were performed using SAS statistical software (Version 8, SAS Institute Inc, Cary, NC).

Characteristics of the study population according to maternal CMV antibody status at the time of the previous pregnancy are shown in Table 1. Overall, 2857 mothers (82.5%) had CMV antibodies at the time of the previous pregnancy, and 604 (17.5%) were seronegative. The majority of both groups were black, although seronegative mothers were more likely to be white (33.4%) than were seropositive mothers (15.8%). Slightly more seronegative mothers (22.0%) compared with seropositive mothers (15.3%) had private health insurance, a difference that was statistically significant (P<.001). Not surprisingly, the initial pregnancy at which serological status was determined was the first pregnancy for more of the seronegative group. Seronegative mothers were younger by less than 1 year in mean age, a difference that was statistically significant (P = .001).

Table Graphic Jump LocationTable 1. Study Population Characteristics by Serostatus During Prior Pregnancy*

Overall, congenital CMV infection occurred in 46 infants (1.3%) born to study mothers. Of 604 newborns born to initially seronegative mothers, congenital CMV infection occurred in 18 (3.0%). In contrast, of 2857 newborns born to immune mothers, congenital CMV infection occurred in 29 (1.0%). In the initially seronegative group, 142 women (23.5%) seroconverted between deliveries. All of the congenital CMV infections among the initially seronegative group occurred in the infants of mothers who seroconverted between pregnancies.

Risk factors for delivering an infant with congenital CMV infection were examined for the entire study population (Table 2). Black race and lower socioeconomic status (Medicaid or no insurance for hospital stay) were both associated with increased risk of congenital CMV infection. However, the 95% CIs for both factors included 1.0. Older maternal age (≥25 years) and gravidity (>2) were associated with decreased risk of congenital CMV infection. The presence of maternal antibody at the previous delivery was highly protective against delivering a future newborn with congenital CMV infection (RR, 0.32; 95% CI, 0.17-0.62).

Table Graphic Jump LocationTable 2. Factors Associated With Delivering a Newborn With Congenital CMV Infection in Multiparous Women

Maternal immune status at previous birth, maternal age, race, insurance status, and gravidity were evaluated in a logistic regression model to simultaneously assess the effects of these factors on the risk of congenital CMV infection. Once maternal immune status at previous birth and maternal age of 25 years or older were included in the model, none of the other potential risk factors changed these estimates and they were not independently associated with congenital CMV infection. Even after adjustment for age, maternal immunity remained strongly protective against congenital CMV infection (adjusted RR, 0.31; 95% CI, 0.17-0.58). Maternal age of 25 years or older remained strongly associated with reduced risk of congenital CMV infection after adjustment for maternal immunity (adjusted RR, 0.19; 95% CI, 0.07-0.49).

This study shows that young women who have immunity to CMV from naturally acquired infection are 69% less likely to give birth to an infant with congenital CMV infection in the future than are those who are initially CMV seronegative. Among mothers CMV seronegative at a previous delivery, seroconversion between deliveries is common (23.5% in this study). When seroconversion occurs between deliveries, the risk of congenital CMV infection is high. We found a rate of congenital CMV infection of 12.7% for offspring of mothers who seroconverted during the interval (average, 3 years) between deliveries.

The major limitation of this study is that it included only multiparous women. Ideally, in testing the ability of immunity from naturally acquired CMV infection to prevent congenital CMV infection, a cohort of young women prior to their first pregnancy would be enrolled after determining their CMV immune status. These women would be followed up through subsequent pregnancies, all offspring would be tested for congenital infection, and maternal seroconversions would be defined by repeat CMV antibody testing. The expense and logistical difficulties associated with enrollment and follow-up of such a cohort of young women would likely make this type of study impossible to conduct. Our study was limited to women who had at least 1 previous pregnancy because this initial pregnancy was used as the starting point for determining immunity to CMV prior to the subsequent pregnancy. The exclusion of younger primiparous women may have led to an underestimation of the proportion of congenital infections due to primary maternal infection, and therefore underestimation of the protective effect of maternal immunity. Since the prevalence of maternal antibody increases rapidly with age in young women, it is likely that a greater proportion of younger women would have been seronegative near the time of their first pregnancy. It is possible that our study has actually underestimated the ability of naturally acquired immunity to prevent future congenital CMV infection by selecting an older multiparous population in which fewer seroconversions will occur.

The current study is the first to compare rates of congenital CMV infection based on maternal immunity status at a point prior to conception. The study population, mothers who had more than 1 pregnancy with delivery of a live newborn at the university hospital, was predominantly black (80%) and young, with a mean age of 24 years. Previous studies of this delivery population have reported a relatively high rate of congenital CMV infection (1.25%), a high rate of primary infection during pregnancy, and the occurrence of congenital CMV infection in women known to have been infected 1 year or more prior to conception.6,9,10 The study population is at high risk for acquisition of CMV between pregnancies with an annualized seroconversion rate of 7.8%, similar to rates reported in day-care workers.1113 Published reports indicate that exposure to young children and sexual activity are important sources of CMV infection for young women.11,12,14,15 Those exposures were not assessed in the current study and the only demographic variable significantly associated with acquisition of CMV among seronegative women was race. Considering the entire study population (seropositive and seronegative women), maternal immunity and older maternal age were associated with protection from congenital CMV infection. None of the other suggested demographic or maternal risk factors were independently associated with congenital CMV infection in this population.

Although the occurrence of congenital CMV infection in offspring of women who are known to have been infected long before conception has been previously reported, the current study probably provides the most accurate estimate for congenital CMV infection rate. Of 2857 immune mothers from a predominantly low-income, young, black population in the United States, 29 (1.0%) transmitted congenital CMV infection. Previous studies from this institution reported a rate of 3.4% in women who were immune prior to conception; this was based on a smaller sample size (n = 208) and a more highly selected study population.6 Other studies have reported high rates (1.2%-2.9%) of congenital CMV infection in populations in which almost all women of childbearing age were seropositive, but they did not define congenital CMV infection rates based on maternal immunity documented prior to conception.1618 However, even a rate of congenital CMV infection of 1.0% is of great concern because the majority of young women from the study population are immune to CMV, and recent studies report that some congenital CMV infections in newborns born to immune mothers are associated with central nervous system disease.1921 A better understanding of the factors that influence occurrence of congenital CMV infection and disease in offspring of immune mothers is needed, both for planning preventive strategies and to estimate the potential effectiveness of vaccines.

Results reported here are of importance in planning strategies for prevention of congenital CMV infection. Based on the reduction in risk of congenital CMV infection associated with maternal immunity, a vaccine that could achieve protection similar to that from immunity from naturally acquired infection would be expected to reduce the rate of congenital CMV infection by at least 70%. Young maternal age was strongly associated with increased risk of congenital CMV infection as has been observed in previous reports.9,22 Our findings along with previous reports indicate that postponing pregnancy until age 20 years or older could substantially reduce the rate of congenital CMV infection.

Stagno S. Cytomegalovirus. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. 4th ed. Philadelphia, Pa: WB Saunders; 1995:312-353.
Fowler KB, Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed?  J Pediatr.1999;135:60-64.
Hicks T, Fowler K, Richardson M, Dahle A, Adams L, Pass R. Congenital cytomegalovirus infection and neonatal auditory screening.  J Pediatr.1993;123:779-782.
Pass RF. Immunization strategy for prevention of congenital cytomegalovirus infection.  Infect Agents Dis.1996;5:240-244.
Stratton K, Durch J, Lawrence R. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: National Academy Press; 2001:476.
Stagno S, Reynolds DW, Huang ES, Thames SD, Smith RJ, Alford CA. Congenital cytomegalovirus infection: occurrence in an immune population.  N Engl J Med.1977;296:1254-1258.
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;326:663-667.
Balcarek KB, Warren W, Smith RJ, Lyon MD, Pass RF. Neonatal screening for congenital cytomegalovirus infection by detection of virus in saliva.  J Infect Dis.1993;167:1433-1436.
Fowler KB, Stagno S, Pass RF. Maternal age and congenital cytomegalovirus infection: screening of two diverse newborn populations, 1980-1990.  J Infect Dis.1993;168:552-556.
Stagno S, Pass RF, Cloud G.  et al.  Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus, and clinical outcome.  JAMA.1986;256:1904-1908.
Adler SP. Cytomegalovirus and child day care: evidence for an increased infection rate among day-care workers.  N Engl J Med.1989;321:1290-1296.
Pass RF, Hutto C, Lyon MD, Cloud G. Increased rate of cytomegalovirus infection among day care center workers.  Pediatr Infect Dis J.1990;9:465-470.
Murph JR, Baron JC, Brown CK, Ebelhack CL, Bale Jr JF. The occupational risk of cytomegalovirus infection among day care providers.  JAMA.1991;265:603-608.
Sohn YM, Oh MK, Balcarek KB, Cloud GA, Pass RF. Cytomegalovirus infection in sexually active adolescents.  J Infect Dis.1991;163:460-463.
Chandler SH, Alexander ER, Holmes KK. Epidemiology of cytomegaloviral infection in a heterogeneous population of pregnant women.  J Infect Dis.1985;152:249-256.
Schopfer K, Lauber E, Krech U. Congenital cytomegalovirus infection in newborn infants of mothers infected before pregnancy.  Arch Dis Child.1978;53:536-539.
Sohn YM, Park KI, Lee C, Han DG, Lee WY. Congenital cytomegalovirus infection in Korean population with very high prevalence of maternal immunity.  J Korean Med Sci.1992;7:47-51.
Mussi-Pinhata MM, Yamamoto AY, Figueiredo LT, Cervi MC, Duarte G. Congenital and perinatal cytomegalovirus infection in infants born to mothers infected with human immunodeficiency virus.  J Pediatr.1998;132:285-290.
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;31:443-457.
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;344:1366-1371.
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.
Preece PM, Tookey P, Ades A, Peckham CS. Congenital cytomegalovirus infection: predisposing maternal factors.  J Epidemiol Community Health.1986;40:205-209.

Figures

Figure. Construction of the Cohort of Multiparous Women
Graphic Jump Location
CMV indicates cytomegalovirus.

Tables

Table Graphic Jump LocationTable 1. Study Population Characteristics by Serostatus During Prior Pregnancy*
Table Graphic Jump LocationTable 2. Factors Associated With Delivering a Newborn With Congenital CMV Infection in Multiparous Women

References

Stagno S. Cytomegalovirus. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. 4th ed. Philadelphia, Pa: WB Saunders; 1995:312-353.
Fowler KB, Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed?  J Pediatr.1999;135:60-64.
Hicks T, Fowler K, Richardson M, Dahle A, Adams L, Pass R. Congenital cytomegalovirus infection and neonatal auditory screening.  J Pediatr.1993;123:779-782.
Pass RF. Immunization strategy for prevention of congenital cytomegalovirus infection.  Infect Agents Dis.1996;5:240-244.
Stratton K, Durch J, Lawrence R. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: National Academy Press; 2001:476.
Stagno S, Reynolds DW, Huang ES, Thames SD, Smith RJ, Alford CA. Congenital cytomegalovirus infection: occurrence in an immune population.  N Engl J Med.1977;296:1254-1258.
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;326:663-667.
Balcarek KB, Warren W, Smith RJ, Lyon MD, Pass RF. Neonatal screening for congenital cytomegalovirus infection by detection of virus in saliva.  J Infect Dis.1993;167:1433-1436.
Fowler KB, Stagno S, Pass RF. Maternal age and congenital cytomegalovirus infection: screening of two diverse newborn populations, 1980-1990.  J Infect Dis.1993;168:552-556.
Stagno S, Pass RF, Cloud G.  et al.  Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus, and clinical outcome.  JAMA.1986;256:1904-1908.
Adler SP. Cytomegalovirus and child day care: evidence for an increased infection rate among day-care workers.  N Engl J Med.1989;321:1290-1296.
Pass RF, Hutto C, Lyon MD, Cloud G. Increased rate of cytomegalovirus infection among day care center workers.  Pediatr Infect Dis J.1990;9:465-470.
Murph JR, Baron JC, Brown CK, Ebelhack CL, Bale Jr JF. The occupational risk of cytomegalovirus infection among day care providers.  JAMA.1991;265:603-608.
Sohn YM, Oh MK, Balcarek KB, Cloud GA, Pass RF. Cytomegalovirus infection in sexually active adolescents.  J Infect Dis.1991;163:460-463.
Chandler SH, Alexander ER, Holmes KK. Epidemiology of cytomegaloviral infection in a heterogeneous population of pregnant women.  J Infect Dis.1985;152:249-256.
Schopfer K, Lauber E, Krech U. Congenital cytomegalovirus infection in newborn infants of mothers infected before pregnancy.  Arch Dis Child.1978;53:536-539.
Sohn YM, Park KI, Lee C, Han DG, Lee WY. Congenital cytomegalovirus infection in Korean population with very high prevalence of maternal immunity.  J Korean Med Sci.1992;7:47-51.
Mussi-Pinhata MM, Yamamoto AY, Figueiredo LT, Cervi MC, Duarte G. Congenital and perinatal cytomegalovirus infection in infants born to mothers infected with human immunodeficiency virus.  J Pediatr.1998;132:285-290.
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;31:443-457.
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;344:1366-1371.
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.
Preece PM, Tookey P, Ades A, Peckham CS. Congenital cytomegalovirus infection: predisposing maternal factors.  J Epidemiol Community Health.1986;40:205-209.
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