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Obstetrics & Gynecology 1999;93:658-660
© 1999 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Increased Risk of Cytomegalovirus Transmission In Utero During Late Gestation

MONIQUE BODÉUS, MD, PhD, CORINNE HUBINONT, MD, PhD and PATRICK GOUBAU, MD, PhD

From the Department of Microbiology, Unit of Virology, and the Department of Obstetrics, Université Catholique de Louvain, Brussels, Belgium.

Address reprint requests to: Monique Bodéus, MD, PhD Department of Microbiology/Virology Catholic University of Louvain Clos Chapelle aux Champs 30, UCL 3055 Brussels 1200 Belgium


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To determine whether the rate of human cytomegalovirus transmission in utero is related to the gestational age at the time of maternal infection.

Methods: One hundred twenty-three pregnant women followed in our units between 1988 and 1998 were studied retrospectively. Each had developed a primary infection with cytomegalovirus evidenced by a seroconversion, confirmed by specific enzyme immunoassays. Infants were diagnosed by urine culture.

Results: Regardless of gestational age at the time of maternal cytomegalovirus seroconversion, the mean rate of intrauterine transmission was 57.5%. There was a statistically significant difference between early seroconversion (during the first trimester) and late seroconversion (during the third trimester) (36.0% versus 77.6%; P < .001). The risk of transmission calculated for seroconversion during the second trimester was intermediate (44.9%).

Conclusion: A statistically significant difference in the rate of intrauterine cytomegalovirus transmission was observed according to the duration of pregnancy at which primary infection occurred. The rate of transmission increased with gestational age.

Cytomegalovirus is considered the most common type of intrauterine viral infection.1 The average incidence of congenital infection is 1% of all live births. Symptomatic infection and fetal damage are mostly due to maternal primary infection.2–4 Among infected newborns, 5–10% are symptomatic at birth (small for gestational age, purpura, hepatosplenomegaly, chorioretinitis, intracranial calcifications, and hearing impairment). Among asymptomatic infants at birth, 10–15% will have late developmental problems.5

The influence of the gestational age at which maternal cytomegalovirus primary infection occurs on the rate of intrauterine transmission has been difficult to ascertain. There have been conflicting opinions, but most reports indicated no significant link between infection in early or late gestation and infection of the infant. The literature is limited to a few reports on small numbers of cases.1,6–9

The purpose of this retrospective study was to relate the time of seroconversion during pregnancy to the rate of intrauterine infection.


   Materials and Methods
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Abstract
 Materials and Methods
Results
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We studied 123 pregnant women followed in our units between 1988 and 1998 for primary cytomegalovirus infections. The two inclusion criteria were documented seroconversion during pregnancy and availability of newborn urine to confirm or disprove intrauterine transmission.

The women were tested serially (every month for 85 women and every trimester for the others). They were assigned to one of three groups according to the gestational age at the time of seroconversion: seroconversion during the first trimester (25 women), second trimester (49 women), or third trimester (49 women).

Sera from the patients at our institution were tested for cytomegalovirus immunoglobulin (Ig)G using a commercial indirect enzyme-linked immunosorbent assay (ELISA) (Enzygnost-CMV-IgG; Behring AG, Marburg, Germany) and for cytomegalovirus IgM by an indirect ELISA (Enzygnost-CMV-IgM; Behring) after removal of rheumatoid factor. The procedure and interpretation of the results (positive or negative) were as recommended by the manufacturer. For the referred patients, maternal seroconversion was first assessed by using various commercial ELISA kits in different laboratories. All were retested and confirmed in our laboratory. The criterion for cytomegalovirus primary infection was the appearance of cytomegalovirus-specific IgG in a previously seronegative patient.

Urine samples were processed immediately in culture, as described.10 Intrauterine infection was assessed by isolating the virus from urine collected within the first 2 weeks of life. The absence of intrauterine infection was assessed by a negative culture. Fisher exact test, {chi}2 test, and odds ratios (ORs) were calculated with Prism 2 software (GraphPad, San Diego, CA).


   Results
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Abstract
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 Results
Discussion
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Sixty-nine infants were infected in utero and 54 were not. Table 1Go shows the distribution of the 123 pregnant women in each group according to the cytomegalovirus status of the newborn (infected or not infected).


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  		Table 1. Congenital Infection According to Gestational Age at Seroconversion
 
The mean rate of intrauterine transmission was 57.5% regardless of gestational age at the time of maternal seroconversion. When the risk of transmission was evaluated according to gestational age at the time of maternal seroconversion, there was a statistically significant difference (P < .001) between early (first trimester) and late (third trimester) seroconversion. The mean rates of transmission were 36.0% and 77.6%, respectively. The OR for transmission in late compared with early seroconversion was 6.14. The risk of transmission was intermediate in cases of seroconversion during the second trimester. The difference in seroconversion was statistically significant between the second and third trimesters but not between the first and second trimesters (Table 2Go).


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  		Table 2. Statistical Assessment of Risk According to Trimester at Seroconversion
 

   Discussion
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Researchers disagree about the influence of the time of maternal cytomegalovirus infection on the outcome of the infant. The literature concerning intrauterine cytomegalovirus transmission is limited, based on few reports of small numbers of cases. A study of nine infected infants among 46 exposed in utero6 found that the virus was transmitted in 20% of cases in the first trimester, 0% in the second, and 40% in the third. The difference between the second and third trimesters was statistically significant. Most other studies used small numbers of cases and showed no statistically significant trend for cytomegalovirus transmission at any particular stage of pregnancy.1,7–9 However, the criteria used to assess maternal primary infection, the techniques used to confirm intrauterine transmission, and the classification by gestational age differed among studies. It is thus difficult to compare the results of these studies because the study groups were usually small and heterogeneous.

The overall rate of intrauterine transmission, regardless of the gestational age at maternal seroconversion, was 57.5%. The rate of transmission is generally agreed to be 20–75%.1,4,6,11–13 When the rate of intrauterine transmission was calculated according to gestational age at the time of maternal seroconversion, there was a statistically significant difference (P < .001) between early and late maternal cytomegalovirus infections, which was confirmed by an OR of 6.14 for late transmissions. Animal models of congenital cytomegalovirus infections have provided evidence supporting this difference. In the guinea pig model, the highest vertical transmission rates occurred in pups from dams that were initially viremic in late gestation.14,15 The very different rates of intrauterine cytomegalovirus transmission reported16–21 could also be explained by our observations and the heterogeneity of gestational age in different studies.

This study provides information on the effects of primary cytomegalovirus infection at different stages of gestation and may help in counseling of women with prenatal cytomegalovirus infections. Our results indicate that the rate of transmission increases with the age of gestation. However, cytomegalovirus congenital infection can occur at any stage of pregnancy, and the rate of disease resulting from intrauterine infection is low (even in the first trimester of pregnancy). Prenatal diagnosis of cytomegalovirus will remain a "longstanding problem still seeking a solution"21 because no treatment or prevention can be offered to pregnant women.


   Footnotes
 
PII S0029-7844(98)00538-9

Received September 10, 1998. Received in revised form November 5, 1998. Accepted November 25, 1998.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 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.[Abstract]

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.[Abstract]

3. Stagno S, Pass RF, Dworsky ME, Henderson RE, Moore EG, Walton PD, et al. Congenital cytomegalovirus infection: The relative importance of primary and recurrent maternal infection. N Engl J Med 1982;306:945–9.[Abstract]

4. Stagno S, Pass RF, Dworsky ME, Alford CA. Maternal cytomegalovirus infection and perinatal transmission. Clin Obstet Gynecol 1982;25:563–76.[Medline]

5. Istas AS, Demmler GJ, Dobbins JG, Stewart JA. Surveillance for congenital cytomegalovirus disease: A report from the National Congenital Cytomegalovirus Disease Registry. Clin Infect Dis 1995;20:665–70.[Medline]

6. Griffiths PD, Baboonian C. A prospective study of primary cytomegalovirus infection during pregnancy: Final report. Br J Obstet Gynaecol 1984;91:307–15.[Medline]

7. Stern H, Tucker SM. Prospective study of cytomegalovirus infection in pregnancy. BMJ 1973;2:268–70.

8. Grant S, Edmond E, Syme JA. Prospective study of cytomegalovirus infection in pregnancy. J Infect 1981;3:24–31.[Medline]

9. Monif GR, Egan EA, Held B, Eitzman DV. The correlation of maternal cytomegalovirus infection during varying stages in gestation with neonatal involvement. J Pediatr 1972;80:17–20.[Medline]

10. Mulongo KN, Lamy ME, Van Lierde M. Requirements for diagnosis of prenatal cytomegalovirus infection by amniotic fluid culture. Clin Diagn Virol 1995;4:231–8.

11. Demmler GJ. Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 1991;13:315–29.[Medline]

12. Nankervis GA, Kumar ML, Cox FE, Gold E. A prospective study of maternal cytomegalovirus infection and its effect on the fetus. Am J Obstet Gynecol 1984;149:435–40.[Medline]

13. Yow MD, Williamson DW, Leeds LJ, Thompson P, Woodward RM, Walmus BF, et al. Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants. Am J Obstet Gynecol 1988;158:1189–95.[Medline]

14. Harrison CJ, Myers MG. Relation of maternal CMV viremia and antibody response to the rate of congenital infection and intrauterine growth retardation. J Med Virol 1990;31:222–8.[Medline]

15. Griffith BP, Hsiung GD. Cytomegalovirus infection in guinea pigs. IV. Maternal infection at different stages of gestation. J Infect Dis 1980;141:787–93.[Medline]

16. Donner C, Liesnard C, Content J, Busine A, Aderca J, Rodesch F. Prenatal diagnosis of 52 pregnancies at risk for congenital cytomegalovirus infection. Obstet Gynecol 1993;82:481–6.[Medline]

17. Hogge WA, Buffone GJ, Hogge JS. Prenatal diagnosis of cytomegalovirus (CMV) infection: A preliminary report. Prenat Diagn 1993;13:131–6.[Medline]

18. Hohlfeld P, Vial Y, Maillard-Brignon C, Vaudaux B, Fawer CL. Cytomegalovirus fetal infection: Prenatal diagnosis. Obstet Gynecol 1991;78:615–8.[Abstract/Free Full Text]

19. Lamy ME, Mulongo KN, Gadisseux JF, Lyon G, Gaudy V, Van Lierde M. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 1992;166:91–4.[Medline]

20. Lynch L, Daffos F, Emanuel D, Giovangrandi Y, Meisel R, Forestier F, et al. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 1991;165:714–8.[Medline]

21. Hagay ZJ, Biran G, Ornoy A, Reece EA. Congenital cytomegalovirus infection: A long-standing problem still seeking a solution. Am J Obstet Gynecol 1996;174:241–5.[Medline]




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