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Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants
Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants Martha D. Yow, MD, Daniel W. Williamson, MD, Leroy J. Leeds, MD, Peter Thompson, MD, Rell M. Woodward, MD, Bethann F. Walmus, MPH, Jerry W. Lester, PhD, Howard R. Six, PhD, and Paul D. Griffiths, MD Houston, Texas In this longitudinal study of cytomegalovirus in 4578 pregnant women of middle/upper socioeconomic status in Houston, 52% had cytomegalovirus antibody when enrolled, and 48% were serologically susceptible. Studies were completed on 3899 mothers and their infants; 2.2% of these women experienced primary cytomegalovirus during pregnancy and 24% of those with primary infection transmitted cytomegalovirus to their infants. Of 22 cytomegalovirus-infected infants, 2 had disease at birth and 20 were asymptomatic. One symptomatic infant (primary maternal infection) has developmental delay. The other (immunocompromised mother with cytomegalovirus antibody before pregnancy) had hepatitis but has no symptoms at 1 year of age. On follow-up, 4 of 16 infants asymptomatic at birth have sequelae (hearing loss in 3, developmental delay in 1). All four were born to mothers with primary cytomegalovirus infection. Infant outcome was not related to trimester of maternal infection. (AM J OssTET GvNECOL 1988;158:1189-95.)
Key words: Cytomegalovirus, congenital infection, congenital deafness
Congenital cytomegalovirus infection continues to be a serious problem in the United States. Approximately I% of all infants in this country are congenitally infected by cytomegalovirus.' Of these, 5% to 10% die or have severe damage (mental retardation, blindness, deafness)."· 3 Of the 95% of infants who are asymptomatic at birth, 15% to 18% will develop problems in infancy or early childhood (deafness, neurological problems, learning difficulties). Cytomegalovirus is the leading infectious cause of mental retardation and congenital deafness in the United States. 4 • 5 Despite the devastating effect of this infection, there is currently no method of prevention or treatment. In October 1981 we initiated a study of the epidemiologic characteristics of cytomegalovirus infection in mothers and their infants. The major purpose was to seek information applicable to prevention of the disease. Our study was designed to match that of other major ongoing studies in the United States and in England to determine whether the problem is comparable in different areas and with different types of populations. In this article we report the results of a 5-year
From the Departments of Pediatrics, Obstetrics and Gynecology, and Microbiology and Immunology, Baylor College of Medicine. This work was supported by the Woman's Hospital of Texas Research and Education Foundation. Received for publication july 30, 1987; revised November 13, 1987; accepted December 15, 1987. Reprint requests: Martha D. Yow, MD, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
longitudinal study of mothers and their infants. The study aims were to determine the risk factors for acquisition of cytomegalovirus during pregnancy, the importance of maternal cytomegalovirus infection as a cause of fetal loss, the role of maternal antibody in protection of the fetus, the influence of gestational age at the time of maternal infection on the severity of fetal involvement, and the immediate and long-term effects of congenital infection in children from birth to 5 years of age.
Material and methods The protocol for this clinical research project was approved by the Baylor College of Medicine Institutional Review Board. The mothers gave written informed consent for their participation and that of their infants. Study population. From October 1981 through April 1986, 4578 pregnant women were enrolled in a prospective study of cytomegalovirus infection in mothers and their infants. These women were all patients (predominantly middle to upper income) of a single obstetric group practice. Demographic data were collected by questionnaire from 1989 of these women, and an obstetric history was provided by their obstetricians. Laboratory data were obtained on 2589 mothers. The women for whom demographic data were collected were predominantly white (85%) and married (97%). The mean age was 28.5 years, with a range of 16 to 41 years. Approximately one third (31%) were primigravid. In order to assess the comparability of this 1189
1190 Yow et al.
May 1988 Am J Obstet Gynecol
Table I. Follow-up of 4578 pregnant women enrolled in study Cytomegalovirus immune status at enrollment Patients
IgG positive
IgG negative
No. of pregnant women No. with complete !aboratory data No. with incomplete laboratory data (total) Spontaneous abortions Fetal deaths Voluntary termination of pregnancy Live births, inadequate specimens Loss to follow-up
2397 1959
2181 1940
438
241
48 10 1
43 3 2
364
178
15
15
group of I989 and the group of 2589 from whom demographic data were not obtained, the following steps were taken. During a IO-month period, data were abstracted from hospital records of all women with demographic data (250) and from a probabilistic sample of 407 women with laboratory data only. Information was collected on maternal age, race, gravidity, number of living offspring, and cytomegalovirus antibody status, as well as on the infant's gestational age at birth, sex, and birth weight. The two groups proved to be similar with respect to all of these factors, except that more of the women with laboratory data only were of nonwhite race, and fewer had living offspring. In the group with laboratory data only, 9.I% were nonwhite as compared with the group with demographic data in which 4.4% were nonwhite. Of the group with laboratory data only, 49% had living offspring, and 61.3% of those with demographic data had living offspring. Collection of specimens. Maternal sera for the determination of cytomegalovirus antibody status were obtained as early in pregnancy as possible. The mean time of collection of the first serum sample was I0.4 weeks (range 5 to 29 weeks). The study design called for the collection of additional sera at IS weeks, at 27 weeks, and at time of delivery. Collection of the ISand 27 -week specimens was not possible from all patients. In all instances maternal and cord sera were collected at delivery. Urine specimens for virus culture were obtained from the infants within the first week of life, the majority within the first 48 hours. When spontaneous abortion, miscarriage, or fetal death occurred, we attempted to obtain a second maternal serum sample promptly and to culture the products of conception. However, this was possible in only three instances. Serologic tests and virus cultures. Sera were tested for cytomegalovirus IgG by enzyme-linked immuno-
sorbent assay and anticomplement immunofluorescence. Cytomegalovirus IgM determinations were performed by enzyme-linked immunosorbent assay (Whitaker, M.A. Bioproducts, Walkersfield, Md.) and by radioimmunoassay. 6 Urine was cultured for cytomegalovirus using a human fibroblast cell line and a standard technique. Definition of maternal immune status. At entry into the investigation, women whose sera contained no cytomegalovirus IgG were defined as nonimmune. Those who had cytomegalovirus IgG but no cytomegalovirus IgM were considered to be immune. Women whose sera contained both IgG and IgM were presumed to be experiencing a primary infection, as Griffiths et aJ.? have reported persistence of cytomegalovirus IgM for I2 to IS weeks after the onset of primary infection in pregnant women, and because IgM has not been detected in instances of reactivation of latent infection during pregnancy. 7 Statistical methods. Comparisons were evaluated by x• analysis or the Student's t test, where appropriate. In order to make a preliminary assessment of which risk factors were significantly associated with primary cytomegalovirus infection, variables were evaluated separately by x• analysis. Then, stepwise logistic regression was used to determine which of the highly interrelated risk factors correlated with primary cytomegalovirus infection in pregnancy. A backward stepwise procedure with maximum likelihood estimation was used. A logistic regression model was fitted twice, once to the variables collected on all seronegative mothers and once to the expanded set of factors available for a subset of these seronegative mothers. Assessment of infants. Infants were examined at birth by their private pediatricians and at I, 4, 6, 9, I2, and IS months and annually thereafter by the members of the Baylor CMV Study Group (developmentalist, neurologist, ophthalmologist, otolaryngologist). Auditory brain stem responses were routinely performed at I month, 6 months, and every I2 to IS months thereafter. Developmental assessment was performed with the Bayley Scales of Infant Development for children ~30 months of age and the McCarthy Scales of Children's Abilities for children >30 months of age. Developmental delay was defined as follows: mild delay, scores I to 2 SD below test means; moderate delay, scores 2 to 3 SD below test means; severe delay, scores >3 SD below test means. An equal number of infants with negative cultures for cytomegalovirus at birth were enrolled as control subjects. These infants were matched for date of birth, sex, race, and socioeconomic status. They were evaluated in the same manner as were the infants with congenital cytomegalovirus infection.
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1191
Table II. Bivariate analysis of maternal risk factors between pregnant women with primary cytomegalovirus infections and pregnant women remaining susceptible Primary cytomegalovirus infection
Risk factors
All susceptible women (n = 94 7) Age <25 yr Nonwhite Multigravid Married Subset of susceptible women (n = 295) :s12 yr education Occupational exposure Presence of children in the home 0 1 2:2 Aged 1-3 Aged 4-7 Aged 12-18 Presence of children by age and type of care Aged 1-3, cared for outside the home Aged 1-3, in organized daycare or preschool Aged 4-7, in elementary school, daycare facility, or preschool
Remaining susceptible
%
No. with factor/ No. of subjects
14/43 3/43 32/43 41/43
33 7 74 95
13/42 7/42
No. with factor/ No. of subjects
I
I
%
p Value*f
177/904 83/898 590/904 882/897
20 9 65 98
0.04 NS NS NS
31 17
36/243 45/253
15 8
0.01 NS
15/42 17/42 10/42 23/42 7/42 3/42
36 40 24 55 17 7
123/253 100/253 30/253 95/253 31/253 5/253
49 40 12 38 12 2
NS NS NS 0.04 NS NS
16/42
38
62/253
25
NS
12/42
29
42/253
17
NS
7/42
17
27/253
11
NS
*x2 analysis. t NS
=
Not significant.
Results
At the time of enrollment 2397 (52%) of the 4578 women had IgG antibody to cytomegalovirus and 2181 (48%) were seronegative. The longitudinal follow-up of the total 4578 pregnant women is shown in Table I. We were able to complete studies on 3899 mother/infant pairs; that is, an adequate set of specimens was available (maternal serum at enrollment and delivery, infant urine specimen at birth). Studies were incomplete in 679 instances because of spontaneous abortion, fetal death, voluntary termination of pregnancy, inadequate specimen collection, or loss to followup. The population base, 3899 mother/infant pairs ( 1959 serologically immune and 1940 serologically susceptible mothers), was used in calculating rates for primary maternal infection and transmission of virus from mother to infant. Primary infection during pregnancy. At enrollment about half of the 3899 mothers ( 1959) had IgG antibody to cytomegalovirus and the remaining half ( 1940) were serologically susceptible. Sera from 1163 of the 1959 women who had cytomegalovirus IgG were tested for the presence of IgM. Of these, 22 (1.9%) had IgM antibody. These women were considered to have primary cytomegalovirus infection. In 21 ( 1.1%) of the serologically susceptible women, serologic conversion
Table III. Logistic regression analysis of factors associated with a primary maternal cytomegalovirus infection Risk factor
Women in total group with complete responses (n = 934) Maternal age <25 yr Women in subset with complete responses (n = 285) Presence in the home of children aged 12-18 Maternal age <25 yr Presence in the home of children aged 1-3
Coefficient (mean ± SE)
Statistical significance
0.69 ± 0.34
0.05
1.50 ± 0.78
0.05
1.22 ± 0.40 0.94 ± 0.36
0.002 0.01
occurred during pregnancy, which made a total of 43 (2.2%) women with primary infection during pregnancy. This figure would have been higher had we been able to perform IgM determinations on all of the women who had cytomegalovirus IgG at enrollment. Risk factors for primary infection during pregnancy. In the first 3 years of the study we collected brief demographic data on 1989 (947 seronegative) women (age, race, marital status, gravidity). During this
1192 Yow et al.
May 1988 Am J Obstet Gynecol
Table IV. Relation of infant outcome to maternal immune status Patient no.
Maternal immune status
Status at birth
Severe hypotonia
Primary infection, 2nd or 3rd trimester
3
Hepatitis Asymptomatic
Reactivated infection, immunocompromised Primary infection, 3rd trimester
4
Asymptomatic
Primary infection, 2nd or 3rd trimester
5
Asymptomatic
6
Asymptomatic
Primary infection, late 1st, 2nd, or 3rd trimester Primary infection, lst trimester
2
time information regarding risk factors for acquisition of cytomegalovirus began to be reported. This information led us to examine additional factors in a subset of 664 (295 seronegative) women. We assessed four risk factors for the occurrence of primary infection in the 94 7 susceptible women and II additional factors in the subset of 295 susceptible women. Comparison by bivariate analysis of these risk factors in the 43 women with primary cytomegalovirus infection during pregnancy and those who remained susceptible is shown in Table II. In the total group of 94 7, the only significant risk factor was age <25 years. In the subset two additional factors were positively related to risk of primary infection. These were that they had ~ 12 years of education and that there were children 1 to 3 years of age in the home. The results of the logistic regression analysis are shown in Table Ill. In the total group the only risk factor independently correlated with primary cytomegalovirus during pregnancy was maternal age <25 years. Analysis of the expanded set of risk factors in the subset of women revealed independent associations between primary infection in pregnancy and maternal age <25 years, the presence of children aged 1 to 3 years in the home, and the presence of children aged 12 to 18 years in the home. There was no evidence of an association between primary infection in pregnancy and the presence of children aged 4 to 7 (years of school entry). The rate of seroconversion was influenced by the order of pregnancy. During the study period we evaluated 86 women through two pregnancies. During the first observed pregnancy the annualized rate of primary infection was 2.7%; in the interim between pregnancies (mean interval 1.23 years) it was 5.8%; and during the second pregnancy, 7.7%. Transmission from mothers to infants
From the longitudinal study population of 3899 mother-infant pairs (immune and nonimmune mothers) there were 17 (0.4%) congenitally infected infants. Seven of the 21 (33%) women who were known to have
Infant follow-up
Severe hypotonia, severe developmental delay Normal at l yr Mild unilateral sensorineural hearing loss Mild unilateral sensorineural hearing loss Moderate developmental delay Severe unilateral sensorineural hearing loss
seroconversion during pregnancy and 3 of 20 (15%) who had cytomegalovirus IgG and IgM at enrollment transmitted cytomegalovirus to their infants. Overall, the rate of congenital cytomegalovirus infection resulting from primary maternal infection was 10/41 (24%). It is possible that some IgM-positive women had primary infections before conceiving, especially those first tested at 5 to 8 weeks of pregnancy. This may explain the lower transmission rate in utero. We were not able to determine the rate of transmission of cytomegalovirus from mother to infant in relation to the time of maternal infection because of the long intervals between serum samples. We could say that transmission occurred from infection that occurred in all three trimesters. From the type of investigation we conducted, it was also not possible to determine how many of the serologically immune women experienced reactivation (or reinfection) during pregnancy. At least three women did so because they transmitted cytomegalovirus to their offspring. Another four congenitally infected infants were offspring of seropositive women enrolled so late in pregnancy(~ 18 weeks' gestation) that the mother's immune status early in pregnancy was unknown. The rate of congenital infection due to reactivation (reinfection) in this Houston population was at least 0.15% (3/ 1959) and could have been as high as 0.36% (711959). Spontaneous abortion and fetal loss. The 1989 women providing demographic data at the onset of pregnancy were followed for outcome, i.e., spontaneous abortion, fetal death, and loss to follow-up. We were able to determine pregnancy outcome on 1959 of the women. Twenty-two of the women with primary infections fell into this group. Among these 22 pregnant women, one pregnancy ended in spontaneous abortion and one in fetal death. We were unable to culture the products of conception in either case, and the fetal tissues were not suitable for histologic examination. Among the 1939 women with no evidence of primary infection, 55 had spontaneous abortions and 12 had fetal deaths. Comparison of pregnancy outcome between the group of women with primary cytomeg-
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alovirus infections and those without infection revealed a positive association between primary maternal infection and fetal death (p < 0.05) but not spontaneous abortion. Assessment of congenitally infected infants. Although the longitudinal study was completed in July 1986 we continued to evaluate additional women and their infants from the same obstetric group practice. From May 1986 through February 1987 there were five congenitally infected infants whose mothers' immune status during pregnancy was known. The information regarding follow-up of the five additional infants is merged with that of the 17 congenitally infected infants from the longitudinal study, which made a total of 22. Fourteen of the 22 congenitally infected infants were born to mothers with primary infection, four were born to immune mothers, and in four the maternal immune status was unknown. Two of the infected infants were symptomatic at birth. One was delivered of a mother with serologic conversion in either the second or third trimester. The mother had symptoms compatible with cytomegalovirus infection in the last trimester but did not have the requisite tests to document that the symptoms were caused by cytomegalovirus. She had cytomegalovirus IgM at the time of delivery. The infant had severe hypotonia at birth, that necessitated gavage feeding for the first month of life. The child is now 2 years old, continues to have hypotonia, and has severe developmental delay. The second child was born to a mother who had cytomegalovirus antibody before pregnancy. She had lupus erythematosus and required large doses of corticosteroids during pregnancy. Tests of stored serial sera showed that she had cytomegalovirus antibody at least 7 years before becoming pregnant. At birt:1 her infant had severe hepatitis caused by cytomegalovirus, proved by histologic examination and virus culture. At the age of 1 year the infant had normal liver function and no evidence of hearing loss or developmental delay. To date, 16 of the 20 infants who were asymptomatic at birth have had both hearing evaluation and developmental testing. The average period of follow-up is 15 months (range 2 to 38 months). Twelve are ~ 12 months of age. Four of these originally asymptomatic children have problems. Three of the 16 (18.7%) have sensorineural hearing loss, and one of the 16 (6%) is moderately developmentally delayed. All four children with sequelae are infants of mothers who had primary cytomegalovirus infection during pregnancy. None of the control children has hearing loss or developmental delay. It is still too early to determine the true status of either the children with congenital cytomegalovirus infection or the children serving as controls. Serial assessment of both groups will be continued until the children are at least 7 years of age.
Cytomegalovirus infection in mothers and infants
1193
Relationship of maternal infection and infant outcome. During pregnancy five of the mothers had signs and symptoms compatible with primary cytomegalovirus infection (fever, fatigue, abnormal liver function tests, lymphocytosis, atypical lymphocytes, positive cytomegalovirus cultures of saliva and urine, cytomegalovirus IgM antibody). Three of the symptomatic mothers had infants with problems (one symptomatic at birth and two with sequelae), but there was no demonstrable significant statistical association between symptomatic maternal illness and damage to the infants. We could not show a relation between the trimester in which the mother was infected and infant outcome (Table IV). Five affected infants were born to mothers with primary cytomegalovirus infection. The mothers acquired cytomegalovirus in the following gestational periods: first trimester, one; second or third trimester, two; third trimester, one; late first, second, or third, one. The most seriously affected infant in the study was born to a mother (patient no. 1, Table IV) whose infection occurred in the second or third trimester. Comment
During the last 15 years a number of prospective longitudinal studies have approached many of the questions addressed by the Houston study. Differences in study design, methods, and populations makes comparison to many of these difficult. The population in this study was roughly comparable with that evaluated by three groups in Britain810 and with the middle-upper socioeconomic patients followed in Birmingham, Ala." The percent age of serologically susceptible women was 48% in our middle-upper socioeconomic population, 45% in the same type of population in Birmingham, and 44%,46%, and 42% in the British studies. A much larger proportion of our population was susceptible than that in populations evaluated by Ahlfors et al.' 2 in Sweden, where only 28% of pregnant women lacked antibody to cytomegalovirus. Despite the differences in prevalence of cytomegalovirus seropositivity, it seems clear that in all geographic areas the serologically immune status of women then they reach childbearing age is related to their age, socioeconomic group, and child-rearing practices, including breast-feeding. Studies of primary cytomegalovirus infection during pregnancy have yielded fairly similar results in serologically susceptible women in all localities: 2.2% in Houston, 1.6% to 3.7% in Birmingham,' 0.7% to 0.09% in Britain, 9 • 13 and 1.2% in Sweden. 12 In the Houston study the risk factors were maternal age <25 years and the presence of children ages 1 to 3 and 12 to 18 years in the home. Mothers being in "high-risk occupations" was not related to seroconversion. Stagno et al.' 4 have published similar findings. They observed that the maternal risk factors were being young and having young
1194 Yow et al.
children in the home. They noted a negative correlation between maternal seroconversion and the mothers' high-intensity contact with children outside the home. However, they found that the fathers' having highintensity contact was a risk factor associated with primary cytomegalovirus infection in the mother. In a London population from all social groups, Griffiths 10 observed that seroconversion was related only to the nonwhite race, whereas the prevalence of cytomegalovirus antibody was also related to social class and maternal age. 10 We noted a progressive increase in the seroconversion rate during the second observed pregnancy as compared with the first and during the interval between the two pregnancies. This increase has been pbserved by others3 and is thought to be the result of the introduction of cytomegalovirus into the family by young children. Obstetricians need to be aware that women with children in the home may be at increased risk for seroconversion during pregnancy. For many years there has been concern about the role of cytomegalovirus in fetal loss. In 1970 Kriel et al. 15 demonstrated that pregnancy wastage can be associated with cytomegalovirus infection. Their investigation was based on histologic determinations and virus isolations from abortuses and stillbirths. In 1984 Griffiths and Baboonian 16 showed an epidemiologic association between maternal cytomegalovirus infection early in pregnancy and excess fetal loss. They were unable to isolate the virus from the abortuses. We found an epidemiologic association between fetal death (>20 weeks' gestation) and primary infection in the mother but found no association with abortion. Each of these studies has been able to identify only small numbers of cases. The rate of transmission from mother to living offspring after primary maternal infection varies from 20% to 50% in different reports. 3 • 9 • 12• 16• 17 When we considered all primary maternal infections, mothers known to undergo seroconversion during pregnancy and those who entered the study with IgG and IgM antibodies, the rate was 24%. In the mothers who were known to have seroconversion during pregnancy, the rate was 33%. The percentage of congenitally infected infants that results from reactivation or reinfection in serologically immune mothers seems to vary depending on the socioeconomic status of the mother. In our study of a middle/upper income population the percentage was low. Only 0.15% of mothers known to be immune had congenitally infected offspring. In London, Griffiths and Baboonian 1" found a rate of 0.14% in women known to be immune before conception. Stagna eta!." report that 0.5% of immune women from a middle-
May 1988 Am J Obstet Gynecol
upper, 1.5% from a lower middle-upper, and 1.5% from a lower income group in Birmingham have congenitally infected children. In all three investigations (Houston, London, and Birmingham), primary maternal infection accounted for a greater proportion of the infected infants than did reactivation of latent infection. In Houston at least two thirds of the infants were infected as a result of primary maternal infection. The lower rate of reactivation in the Houston study may have been related to the mothers' being somewhat older than those in the Birmingham studies, as reactivation of cytomegalovirus seems to diminish with increasing age between 14 and 30 years. Conflicting opinions have been expressed regarding the influence of the time of maternal infection on the outcome in the infants. 3 • 12 • 17 • 20 Some investigators stress the importance of infection early in pregnancy, others in the second trimester, and still others in the third trimester. Preece et al. 20 observed children with neurological defects after maternal infection in all three trimesters. We were not able to show a relation between the trimester in which the mother was infected and the degree of damage to the infant. Our investigation suffered from the problem that is common to most longitudinal studies of cytomegalovirus infection in mothers and their infants, that is, the difficulty in consistently obtaining maternal sera at appropriate intervals. It is our impression that insufficient data exist to state that maternal infection is more dangerous in one trimester than another. Physicians and parents have tended to equate cytomegalovirus maternal infection with rubella maternal infection, which creates a widely held view that maternal cytomegalovirus infection after the first trimester has a greatly reduced risk. We feel that this is a misleading concept for the doctor and the parents. One of the most important reasons for conducting prospective studies of cytomegalovirus infection during pregnancy is to define the role of maternal immunity in protection of the fetus. The numbers in our study are too small to answer this question but are useful when added to the cumulative results of similar prospective investigations. 3 • 9 • 12 · 16• 17 These results indicate that in the vast majority of instances maternal immunity protects the infant from disease, if not from infection. There have been only two previous reports of affected infants born to mothers who were seropositive before pregnancy. 12 • 21 Ample evidence exists now that it is desirable for women to have immunity to cytomegalovirus before they become pregnant. Use of a vaccine seems the only logical approach to prevention of congenital cytomegalovirus infection. In the United States the development and use of a suitable vaccine is urgently needed because currently large numbers of nonimmune women of childbearing age are being exposed
Cytomegalovirus infection in mothers and infants
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and also large numbers of young children who are infected and shedding cytomegalovirus for prolonged periods of time. Sara G. Reis, RN, Najia H. White, MD, Romelia A. May, Mary T. Neal, MD, John B. Ross, MD, Mark A. Jacobs, MD, John F. Irwin, MD, and Larry H. Taber, MD, contributed to the study.
10. 11.
12.
REFERENCES I. Conboy TJ, Pass RF, Stagno S, et al. Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection. Pediatrics 1986;77: 801-6. 2. Williamson WD, Desmond MM, LaFevers N, Taber LH, Catlin Fl, Weaver TG. Symptomatic congenital cytomegalovirus: disorders of language, learning, and hearing. Am] Dis Child 1982;136:902-5. 3. Stagno S, Pass RF, Cloud G, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus and clinical outcome. JAMA 1986;256: 1904-8. 4. Hanshaw JB. On deafness, cytomegalovirus and neonatal screening. AmJ Dis Child 1982;126:886-7. 5. Alford CA, Stagno S, Pass RF, Huang E-S. Epidemiology of cytomegalovirus of man. In: Nahmiar A, Dowdle W, Schenage R, eds. The human herpesviruses. Amsterdam: Elsevier, 1982:159-71. 6. Demmler G, Six H, Hurst M, Yow M. Enzyme-linked immunosorbent assay for the detection of IgM-class antibodies against cytomegalovirus. J Infect Dis 1986; 153: 1152-5. 7. Griffiths PD, Stagno S, Pass RF, Smith RJ, Alford CA. Infection with cytomegalovirus during pregnancy: specific IgM antibodies as a marker of recent primary infection. J Infect Dis 1982; 145:64 7-53. 8. Peckham CS, Chin KS, Coleman JC, et al. Cytomegalovirus infection in pregnancy: preliminary findings from a prospective study. Lancet 1983;1:1352-5. 9. Grant S, Edmond E, Syme J. A prospective study of cy-
13. 14. 15. 16. 17. 18. 19. 20. 21.
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tomegalovirus infection in pregnancy: laboratory evidence of congenital infection following maternal primary and reactivated infection. J Infect 1981;3:24-31. Griffiths P, Baboonian C, Ashby D. The demographic characteristics of pregnant women infected with cytomegalovirus. Intj Epidemiol 1985;14:447-52. Stagno S, Pass RF, Dworsky ME, et al. Congenital cytomegalovirus infection: the relative importance of primary and recurrent maternal infection. N Eng! J Med 1982; 306:945-9. Ahlfors K, lvarsson SA, Johnsson T, Svanberg L. Primary and secondary maternal cytomegalovirus infections and their relation to congenital infection: analysis of maternal sera. Acta Paediatr Scand 1982;71:109-13. Griffiths PD, Campbell-Benzie A, Heath RB. A prospective study of primary cytomegalovirus infection in pregnant women. Br J Obstet Gynaecol 1980;87:308-14. Stagno S, Cloud G, Pass RF, Britt WJ, Alford CA. Factors associated with primary cytomegalovirus infection during pregnancy.] Med Viroll984;13:347-53. Kriel RL, Gates GA, Wulff H. Powell N, PolandJD, Chin TDY. Cytomegalovirus isolations associated with pregnancy wastage. AM j 0BSTET GYNECOL 1970; 106:885-92. Griffiths PD, Baboonian C. A prospective study of primary cytomegalovirus infection during pregnancy: a final report. Br J Obstet Gynaecol 1984;91:307-15. Stern H, Tucker SM. Prospective study of cytomegalovirus infection in pregnancy. Br Med J 1973;2:268-270. Griffiths PD, Baboonian C. Intrauterine transmission of cytomegalovirus in women known to be immune before conception. J Hyg (Camb) 1984;92:89-95. Nankervis GA, Kumar JL, Cox FE, Gold E. A prospective study of maternal cytomegalovirus infection and its effect on the fetus. AM j 0BSTET GYNECOL 1984; 149:435-40. Preece PM, Pearl KN, Peckham CS. Congenital cytomegalovirus infection. Arch Dis Child 1984;59: 1120-6. Rutter D, Griffiths P, Trompeter RS. Cytomegalic inclusion disease after recurrent maternal infection. Lancet 1985;2: 1182.
A complete list of references is available on request from the authors.
Key words: Cytomegalovirus, congenital infection, congenital deafness
Congenital cytomegalovirus infection continues to be a serious problem in the United States. Approximately I% of all infants in this country are congenitally infected by cytomegalovirus.' Of these, 5% to 10% die or have severe damage (mental retardation, blindness, deafness)."· 3 Of the 95% of infants who are asymptomatic at birth, 15% to 18% will develop problems in infancy or early childhood (deafness, neurological problems, learning difficulties). Cytomegalovirus is the leading infectious cause of mental retardation and congenital deafness in the United States. 4 • 5 Despite the devastating effect of this infection, there is currently no method of prevention or treatment. In October 1981 we initiated a study of the epidemiologic characteristics of cytomegalovirus infection in mothers and their infants. The major purpose was to seek information applicable to prevention of the disease. Our study was designed to match that of other major ongoing studies in the United States and in England to determine whether the problem is comparable in different areas and with different types of populations. In this article we report the results of a 5-year
From the Departments of Pediatrics, Obstetrics and Gynecology, and Microbiology and Immunology, Baylor College of Medicine. This work was supported by the Woman's Hospital of Texas Research and Education Foundation. Received for publication july 30, 1987; revised November 13, 1987; accepted December 15, 1987. Reprint requests: Martha D. Yow, MD, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
longitudinal study of mothers and their infants. The study aims were to determine the risk factors for acquisition of cytomegalovirus during pregnancy, the importance of maternal cytomegalovirus infection as a cause of fetal loss, the role of maternal antibody in protection of the fetus, the influence of gestational age at the time of maternal infection on the severity of fetal involvement, and the immediate and long-term effects of congenital infection in children from birth to 5 years of age.
Material and methods The protocol for this clinical research project was approved by the Baylor College of Medicine Institutional Review Board. The mothers gave written informed consent for their participation and that of their infants. Study population. From October 1981 through April 1986, 4578 pregnant women were enrolled in a prospective study of cytomegalovirus infection in mothers and their infants. These women were all patients (predominantly middle to upper income) of a single obstetric group practice. Demographic data were collected by questionnaire from 1989 of these women, and an obstetric history was provided by their obstetricians. Laboratory data were obtained on 2589 mothers. The women for whom demographic data were collected were predominantly white (85%) and married (97%). The mean age was 28.5 years, with a range of 16 to 41 years. Approximately one third (31%) were primigravid. In order to assess the comparability of this 1189
1190 Yow et al.
May 1988 Am J Obstet Gynecol
Table I. Follow-up of 4578 pregnant women enrolled in study Cytomegalovirus immune status at enrollment Patients
IgG positive
IgG negative
No. of pregnant women No. with complete !aboratory data No. with incomplete laboratory data (total) Spontaneous abortions Fetal deaths Voluntary termination of pregnancy Live births, inadequate specimens Loss to follow-up
2397 1959
2181 1940
438
241
48 10 1
43 3 2
364
178
15
15
group of I989 and the group of 2589 from whom demographic data were not obtained, the following steps were taken. During a IO-month period, data were abstracted from hospital records of all women with demographic data (250) and from a probabilistic sample of 407 women with laboratory data only. Information was collected on maternal age, race, gravidity, number of living offspring, and cytomegalovirus antibody status, as well as on the infant's gestational age at birth, sex, and birth weight. The two groups proved to be similar with respect to all of these factors, except that more of the women with laboratory data only were of nonwhite race, and fewer had living offspring. In the group with laboratory data only, 9.I% were nonwhite as compared with the group with demographic data in which 4.4% were nonwhite. Of the group with laboratory data only, 49% had living offspring, and 61.3% of those with demographic data had living offspring. Collection of specimens. Maternal sera for the determination of cytomegalovirus antibody status were obtained as early in pregnancy as possible. The mean time of collection of the first serum sample was I0.4 weeks (range 5 to 29 weeks). The study design called for the collection of additional sera at IS weeks, at 27 weeks, and at time of delivery. Collection of the ISand 27 -week specimens was not possible from all patients. In all instances maternal and cord sera were collected at delivery. Urine specimens for virus culture were obtained from the infants within the first week of life, the majority within the first 48 hours. When spontaneous abortion, miscarriage, or fetal death occurred, we attempted to obtain a second maternal serum sample promptly and to culture the products of conception. However, this was possible in only three instances. Serologic tests and virus cultures. Sera were tested for cytomegalovirus IgG by enzyme-linked immuno-
sorbent assay and anticomplement immunofluorescence. Cytomegalovirus IgM determinations were performed by enzyme-linked immunosorbent assay (Whitaker, M.A. Bioproducts, Walkersfield, Md.) and by radioimmunoassay. 6 Urine was cultured for cytomegalovirus using a human fibroblast cell line and a standard technique. Definition of maternal immune status. At entry into the investigation, women whose sera contained no cytomegalovirus IgG were defined as nonimmune. Those who had cytomegalovirus IgG but no cytomegalovirus IgM were considered to be immune. Women whose sera contained both IgG and IgM were presumed to be experiencing a primary infection, as Griffiths et aJ.? have reported persistence of cytomegalovirus IgM for I2 to IS weeks after the onset of primary infection in pregnant women, and because IgM has not been detected in instances of reactivation of latent infection during pregnancy. 7 Statistical methods. Comparisons were evaluated by x• analysis or the Student's t test, where appropriate. In order to make a preliminary assessment of which risk factors were significantly associated with primary cytomegalovirus infection, variables were evaluated separately by x• analysis. Then, stepwise logistic regression was used to determine which of the highly interrelated risk factors correlated with primary cytomegalovirus infection in pregnancy. A backward stepwise procedure with maximum likelihood estimation was used. A logistic regression model was fitted twice, once to the variables collected on all seronegative mothers and once to the expanded set of factors available for a subset of these seronegative mothers. Assessment of infants. Infants were examined at birth by their private pediatricians and at I, 4, 6, 9, I2, and IS months and annually thereafter by the members of the Baylor CMV Study Group (developmentalist, neurologist, ophthalmologist, otolaryngologist). Auditory brain stem responses were routinely performed at I month, 6 months, and every I2 to IS months thereafter. Developmental assessment was performed with the Bayley Scales of Infant Development for children ~30 months of age and the McCarthy Scales of Children's Abilities for children >30 months of age. Developmental delay was defined as follows: mild delay, scores I to 2 SD below test means; moderate delay, scores 2 to 3 SD below test means; severe delay, scores >3 SD below test means. An equal number of infants with negative cultures for cytomegalovirus at birth were enrolled as control subjects. These infants were matched for date of birth, sex, race, and socioeconomic status. They were evaluated in the same manner as were the infants with congenital cytomegalovirus infection.
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1191
Table II. Bivariate analysis of maternal risk factors between pregnant women with primary cytomegalovirus infections and pregnant women remaining susceptible Primary cytomegalovirus infection
Risk factors
All susceptible women (n = 94 7) Age <25 yr Nonwhite Multigravid Married Subset of susceptible women (n = 295) :s12 yr education Occupational exposure Presence of children in the home 0 1 2:2 Aged 1-3 Aged 4-7 Aged 12-18 Presence of children by age and type of care Aged 1-3, cared for outside the home Aged 1-3, in organized daycare or preschool Aged 4-7, in elementary school, daycare facility, or preschool
Remaining susceptible
%
No. with factor/ No. of subjects
14/43 3/43 32/43 41/43
33 7 74 95
13/42 7/42
No. with factor/ No. of subjects
I
I
%
p Value*f
177/904 83/898 590/904 882/897
20 9 65 98
0.04 NS NS NS
31 17
36/243 45/253
15 8
0.01 NS
15/42 17/42 10/42 23/42 7/42 3/42
36 40 24 55 17 7
123/253 100/253 30/253 95/253 31/253 5/253
49 40 12 38 12 2
NS NS NS 0.04 NS NS
16/42
38
62/253
25
NS
12/42
29
42/253
17
NS
7/42
17
27/253
11
NS
*x2 analysis. t NS
=
Not significant.
Results
At the time of enrollment 2397 (52%) of the 4578 women had IgG antibody to cytomegalovirus and 2181 (48%) were seronegative. The longitudinal follow-up of the total 4578 pregnant women is shown in Table I. We were able to complete studies on 3899 mother/infant pairs; that is, an adequate set of specimens was available (maternal serum at enrollment and delivery, infant urine specimen at birth). Studies were incomplete in 679 instances because of spontaneous abortion, fetal death, voluntary termination of pregnancy, inadequate specimen collection, or loss to followup. The population base, 3899 mother/infant pairs ( 1959 serologically immune and 1940 serologically susceptible mothers), was used in calculating rates for primary maternal infection and transmission of virus from mother to infant. Primary infection during pregnancy. At enrollment about half of the 3899 mothers ( 1959) had IgG antibody to cytomegalovirus and the remaining half ( 1940) were serologically susceptible. Sera from 1163 of the 1959 women who had cytomegalovirus IgG were tested for the presence of IgM. Of these, 22 (1.9%) had IgM antibody. These women were considered to have primary cytomegalovirus infection. In 21 ( 1.1%) of the serologically susceptible women, serologic conversion
Table III. Logistic regression analysis of factors associated with a primary maternal cytomegalovirus infection Risk factor
Women in total group with complete responses (n = 934) Maternal age <25 yr Women in subset with complete responses (n = 285) Presence in the home of children aged 12-18 Maternal age <25 yr Presence in the home of children aged 1-3
Coefficient (mean ± SE)
Statistical significance
0.69 ± 0.34
0.05
1.50 ± 0.78
0.05
1.22 ± 0.40 0.94 ± 0.36
0.002 0.01
occurred during pregnancy, which made a total of 43 (2.2%) women with primary infection during pregnancy. This figure would have been higher had we been able to perform IgM determinations on all of the women who had cytomegalovirus IgG at enrollment. Risk factors for primary infection during pregnancy. In the first 3 years of the study we collected brief demographic data on 1989 (947 seronegative) women (age, race, marital status, gravidity). During this
1192 Yow et al.
May 1988 Am J Obstet Gynecol
Table IV. Relation of infant outcome to maternal immune status Patient no.
Maternal immune status
Status at birth
Severe hypotonia
Primary infection, 2nd or 3rd trimester
3
Hepatitis Asymptomatic
Reactivated infection, immunocompromised Primary infection, 3rd trimester
4
Asymptomatic
Primary infection, 2nd or 3rd trimester
5
Asymptomatic
6
Asymptomatic
Primary infection, late 1st, 2nd, or 3rd trimester Primary infection, lst trimester
2
time information regarding risk factors for acquisition of cytomegalovirus began to be reported. This information led us to examine additional factors in a subset of 664 (295 seronegative) women. We assessed four risk factors for the occurrence of primary infection in the 94 7 susceptible women and II additional factors in the subset of 295 susceptible women. Comparison by bivariate analysis of these risk factors in the 43 women with primary cytomegalovirus infection during pregnancy and those who remained susceptible is shown in Table II. In the total group of 94 7, the only significant risk factor was age <25 years. In the subset two additional factors were positively related to risk of primary infection. These were that they had ~ 12 years of education and that there were children 1 to 3 years of age in the home. The results of the logistic regression analysis are shown in Table Ill. In the total group the only risk factor independently correlated with primary cytomegalovirus during pregnancy was maternal age <25 years. Analysis of the expanded set of risk factors in the subset of women revealed independent associations between primary infection in pregnancy and maternal age <25 years, the presence of children aged 1 to 3 years in the home, and the presence of children aged 12 to 18 years in the home. There was no evidence of an association between primary infection in pregnancy and the presence of children aged 4 to 7 (years of school entry). The rate of seroconversion was influenced by the order of pregnancy. During the study period we evaluated 86 women through two pregnancies. During the first observed pregnancy the annualized rate of primary infection was 2.7%; in the interim between pregnancies (mean interval 1.23 years) it was 5.8%; and during the second pregnancy, 7.7%. Transmission from mothers to infants
From the longitudinal study population of 3899 mother-infant pairs (immune and nonimmune mothers) there were 17 (0.4%) congenitally infected infants. Seven of the 21 (33%) women who were known to have
Infant follow-up
Severe hypotonia, severe developmental delay Normal at l yr Mild unilateral sensorineural hearing loss Mild unilateral sensorineural hearing loss Moderate developmental delay Severe unilateral sensorineural hearing loss
seroconversion during pregnancy and 3 of 20 (15%) who had cytomegalovirus IgG and IgM at enrollment transmitted cytomegalovirus to their infants. Overall, the rate of congenital cytomegalovirus infection resulting from primary maternal infection was 10/41 (24%). It is possible that some IgM-positive women had primary infections before conceiving, especially those first tested at 5 to 8 weeks of pregnancy. This may explain the lower transmission rate in utero. We were not able to determine the rate of transmission of cytomegalovirus from mother to infant in relation to the time of maternal infection because of the long intervals between serum samples. We could say that transmission occurred from infection that occurred in all three trimesters. From the type of investigation we conducted, it was also not possible to determine how many of the serologically immune women experienced reactivation (or reinfection) during pregnancy. At least three women did so because they transmitted cytomegalovirus to their offspring. Another four congenitally infected infants were offspring of seropositive women enrolled so late in pregnancy(~ 18 weeks' gestation) that the mother's immune status early in pregnancy was unknown. The rate of congenital infection due to reactivation (reinfection) in this Houston population was at least 0.15% (3/ 1959) and could have been as high as 0.36% (711959). Spontaneous abortion and fetal loss. The 1989 women providing demographic data at the onset of pregnancy were followed for outcome, i.e., spontaneous abortion, fetal death, and loss to follow-up. We were able to determine pregnancy outcome on 1959 of the women. Twenty-two of the women with primary infections fell into this group. Among these 22 pregnant women, one pregnancy ended in spontaneous abortion and one in fetal death. We were unable to culture the products of conception in either case, and the fetal tissues were not suitable for histologic examination. Among the 1939 women with no evidence of primary infection, 55 had spontaneous abortions and 12 had fetal deaths. Comparison of pregnancy outcome between the group of women with primary cytomeg-
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alovirus infections and those without infection revealed a positive association between primary maternal infection and fetal death (p < 0.05) but not spontaneous abortion. Assessment of congenitally infected infants. Although the longitudinal study was completed in July 1986 we continued to evaluate additional women and their infants from the same obstetric group practice. From May 1986 through February 1987 there were five congenitally infected infants whose mothers' immune status during pregnancy was known. The information regarding follow-up of the five additional infants is merged with that of the 17 congenitally infected infants from the longitudinal study, which made a total of 22. Fourteen of the 22 congenitally infected infants were born to mothers with primary infection, four were born to immune mothers, and in four the maternal immune status was unknown. Two of the infected infants were symptomatic at birth. One was delivered of a mother with serologic conversion in either the second or third trimester. The mother had symptoms compatible with cytomegalovirus infection in the last trimester but did not have the requisite tests to document that the symptoms were caused by cytomegalovirus. She had cytomegalovirus IgM at the time of delivery. The infant had severe hypotonia at birth, that necessitated gavage feeding for the first month of life. The child is now 2 years old, continues to have hypotonia, and has severe developmental delay. The second child was born to a mother who had cytomegalovirus antibody before pregnancy. She had lupus erythematosus and required large doses of corticosteroids during pregnancy. Tests of stored serial sera showed that she had cytomegalovirus antibody at least 7 years before becoming pregnant. At birt:1 her infant had severe hepatitis caused by cytomegalovirus, proved by histologic examination and virus culture. At the age of 1 year the infant had normal liver function and no evidence of hearing loss or developmental delay. To date, 16 of the 20 infants who were asymptomatic at birth have had both hearing evaluation and developmental testing. The average period of follow-up is 15 months (range 2 to 38 months). Twelve are ~ 12 months of age. Four of these originally asymptomatic children have problems. Three of the 16 (18.7%) have sensorineural hearing loss, and one of the 16 (6%) is moderately developmentally delayed. All four children with sequelae are infants of mothers who had primary cytomegalovirus infection during pregnancy. None of the control children has hearing loss or developmental delay. It is still too early to determine the true status of either the children with congenital cytomegalovirus infection or the children serving as controls. Serial assessment of both groups will be continued until the children are at least 7 years of age.
Cytomegalovirus infection in mothers and infants
1193
Relationship of maternal infection and infant outcome. During pregnancy five of the mothers had signs and symptoms compatible with primary cytomegalovirus infection (fever, fatigue, abnormal liver function tests, lymphocytosis, atypical lymphocytes, positive cytomegalovirus cultures of saliva and urine, cytomegalovirus IgM antibody). Three of the symptomatic mothers had infants with problems (one symptomatic at birth and two with sequelae), but there was no demonstrable significant statistical association between symptomatic maternal illness and damage to the infants. We could not show a relation between the trimester in which the mother was infected and infant outcome (Table IV). Five affected infants were born to mothers with primary cytomegalovirus infection. The mothers acquired cytomegalovirus in the following gestational periods: first trimester, one; second or third trimester, two; third trimester, one; late first, second, or third, one. The most seriously affected infant in the study was born to a mother (patient no. 1, Table IV) whose infection occurred in the second or third trimester. Comment
During the last 15 years a number of prospective longitudinal studies have approached many of the questions addressed by the Houston study. Differences in study design, methods, and populations makes comparison to many of these difficult. The population in this study was roughly comparable with that evaluated by three groups in Britain810 and with the middle-upper socioeconomic patients followed in Birmingham, Ala." The percent age of serologically susceptible women was 48% in our middle-upper socioeconomic population, 45% in the same type of population in Birmingham, and 44%,46%, and 42% in the British studies. A much larger proportion of our population was susceptible than that in populations evaluated by Ahlfors et al.' 2 in Sweden, where only 28% of pregnant women lacked antibody to cytomegalovirus. Despite the differences in prevalence of cytomegalovirus seropositivity, it seems clear that in all geographic areas the serologically immune status of women then they reach childbearing age is related to their age, socioeconomic group, and child-rearing practices, including breast-feeding. Studies of primary cytomegalovirus infection during pregnancy have yielded fairly similar results in serologically susceptible women in all localities: 2.2% in Houston, 1.6% to 3.7% in Birmingham,' 0.7% to 0.09% in Britain, 9 • 13 and 1.2% in Sweden. 12 In the Houston study the risk factors were maternal age <25 years and the presence of children ages 1 to 3 and 12 to 18 years in the home. Mothers being in "high-risk occupations" was not related to seroconversion. Stagno et al.' 4 have published similar findings. They observed that the maternal risk factors were being young and having young
1194 Yow et al.
children in the home. They noted a negative correlation between maternal seroconversion and the mothers' high-intensity contact with children outside the home. However, they found that the fathers' having highintensity contact was a risk factor associated with primary cytomegalovirus infection in the mother. In a London population from all social groups, Griffiths 10 observed that seroconversion was related only to the nonwhite race, whereas the prevalence of cytomegalovirus antibody was also related to social class and maternal age. 10 We noted a progressive increase in the seroconversion rate during the second observed pregnancy as compared with the first and during the interval between the two pregnancies. This increase has been pbserved by others3 and is thought to be the result of the introduction of cytomegalovirus into the family by young children. Obstetricians need to be aware that women with children in the home may be at increased risk for seroconversion during pregnancy. For many years there has been concern about the role of cytomegalovirus in fetal loss. In 1970 Kriel et al. 15 demonstrated that pregnancy wastage can be associated with cytomegalovirus infection. Their investigation was based on histologic determinations and virus isolations from abortuses and stillbirths. In 1984 Griffiths and Baboonian 16 showed an epidemiologic association between maternal cytomegalovirus infection early in pregnancy and excess fetal loss. They were unable to isolate the virus from the abortuses. We found an epidemiologic association between fetal death (>20 weeks' gestation) and primary infection in the mother but found no association with abortion. Each of these studies has been able to identify only small numbers of cases. The rate of transmission from mother to living offspring after primary maternal infection varies from 20% to 50% in different reports. 3 • 9 • 12• 16• 17 When we considered all primary maternal infections, mothers known to undergo seroconversion during pregnancy and those who entered the study with IgG and IgM antibodies, the rate was 24%. In the mothers who were known to have seroconversion during pregnancy, the rate was 33%. The percentage of congenitally infected infants that results from reactivation or reinfection in serologically immune mothers seems to vary depending on the socioeconomic status of the mother. In our study of a middle/upper income population the percentage was low. Only 0.15% of mothers known to be immune had congenitally infected offspring. In London, Griffiths and Baboonian 1" found a rate of 0.14% in women known to be immune before conception. Stagna eta!." report that 0.5% of immune women from a middle-
May 1988 Am J Obstet Gynecol
upper, 1.5% from a lower middle-upper, and 1.5% from a lower income group in Birmingham have congenitally infected children. In all three investigations (Houston, London, and Birmingham), primary maternal infection accounted for a greater proportion of the infected infants than did reactivation of latent infection. In Houston at least two thirds of the infants were infected as a result of primary maternal infection. The lower rate of reactivation in the Houston study may have been related to the mothers' being somewhat older than those in the Birmingham studies, as reactivation of cytomegalovirus seems to diminish with increasing age between 14 and 30 years. Conflicting opinions have been expressed regarding the influence of the time of maternal infection on the outcome in the infants. 3 • 12 • 17 • 20 Some investigators stress the importance of infection early in pregnancy, others in the second trimester, and still others in the third trimester. Preece et al. 20 observed children with neurological defects after maternal infection in all three trimesters. We were not able to show a relation between the trimester in which the mother was infected and the degree of damage to the infant. Our investigation suffered from the problem that is common to most longitudinal studies of cytomegalovirus infection in mothers and their infants, that is, the difficulty in consistently obtaining maternal sera at appropriate intervals. It is our impression that insufficient data exist to state that maternal infection is more dangerous in one trimester than another. Physicians and parents have tended to equate cytomegalovirus maternal infection with rubella maternal infection, which creates a widely held view that maternal cytomegalovirus infection after the first trimester has a greatly reduced risk. We feel that this is a misleading concept for the doctor and the parents. One of the most important reasons for conducting prospective studies of cytomegalovirus infection during pregnancy is to define the role of maternal immunity in protection of the fetus. The numbers in our study are too small to answer this question but are useful when added to the cumulative results of similar prospective investigations. 3 • 9 • 12 · 16• 17 These results indicate that in the vast majority of instances maternal immunity protects the infant from disease, if not from infection. There have been only two previous reports of affected infants born to mothers who were seropositive before pregnancy. 12 • 21 Ample evidence exists now that it is desirable for women to have immunity to cytomegalovirus before they become pregnant. Use of a vaccine seems the only logical approach to prevention of congenital cytomegalovirus infection. In the United States the development and use of a suitable vaccine is urgently needed because currently large numbers of nonimmune women of childbearing age are being exposed
Cytomegalovirus infection in mothers and infants
Volume 158 Number 5
and also large numbers of young children who are infected and shedding cytomegalovirus for prolonged periods of time. Sara G. Reis, RN, Najia H. White, MD, Romelia A. May, Mary T. Neal, MD, John B. Ross, MD, Mark A. Jacobs, MD, John F. Irwin, MD, and Larry H. Taber, MD, contributed to the study.
10. 11.
12.
REFERENCES I. Conboy TJ, Pass RF, Stagno S, et al. Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection. Pediatrics 1986;77: 801-6. 2. Williamson WD, Desmond MM, LaFevers N, Taber LH, Catlin Fl, Weaver TG. Symptomatic congenital cytomegalovirus: disorders of language, learning, and hearing. Am] Dis Child 1982;136:902-5. 3. Stagno S, Pass RF, Cloud G, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus and clinical outcome. JAMA 1986;256: 1904-8. 4. Hanshaw JB. On deafness, cytomegalovirus and neonatal screening. AmJ Dis Child 1982;126:886-7. 5. Alford CA, Stagno S, Pass RF, Huang E-S. Epidemiology of cytomegalovirus of man. In: Nahmiar A, Dowdle W, Schenage R, eds. The human herpesviruses. Amsterdam: Elsevier, 1982:159-71. 6. Demmler G, Six H, Hurst M, Yow M. Enzyme-linked immunosorbent assay for the detection of IgM-class antibodies against cytomegalovirus. J Infect Dis 1986; 153: 1152-5. 7. Griffiths PD, Stagno S, Pass RF, Smith RJ, Alford CA. Infection with cytomegalovirus during pregnancy: specific IgM antibodies as a marker of recent primary infection. J Infect Dis 1982; 145:64 7-53. 8. Peckham CS, Chin KS, Coleman JC, et al. Cytomegalovirus infection in pregnancy: preliminary findings from a prospective study. Lancet 1983;1:1352-5. 9. Grant S, Edmond E, Syme J. A prospective study of cy-
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tomegalovirus infection in pregnancy: laboratory evidence of congenital infection following maternal primary and reactivated infection. J Infect 1981;3:24-31. Griffiths P, Baboonian C, Ashby D. The demographic characteristics of pregnant women infected with cytomegalovirus. Intj Epidemiol 1985;14:447-52. Stagno S, Pass RF, Dworsky ME, et al. Congenital cytomegalovirus infection: the relative importance of primary and recurrent maternal infection. N Eng! J Med 1982; 306:945-9. Ahlfors K, lvarsson SA, Johnsson T, Svanberg L. Primary and secondary maternal cytomegalovirus infections and their relation to congenital infection: analysis of maternal sera. Acta Paediatr Scand 1982;71:109-13. Griffiths PD, Campbell-Benzie A, Heath RB. A prospective study of primary cytomegalovirus infection in pregnant women. Br J Obstet Gynaecol 1980;87:308-14. Stagno S, Cloud G, Pass RF, Britt WJ, Alford CA. Factors associated with primary cytomegalovirus infection during pregnancy.] Med Viroll984;13:347-53. Kriel RL, Gates GA, Wulff H. Powell N, PolandJD, Chin TDY. Cytomegalovirus isolations associated with pregnancy wastage. AM j 0BSTET GYNECOL 1970; 106:885-92. Griffiths PD, Baboonian C. A prospective study of primary cytomegalovirus infection during pregnancy: a final report. Br J Obstet Gynaecol 1984;91:307-15. Stern H, Tucker SM. Prospective study of cytomegalovirus infection in pregnancy. Br Med J 1973;2:268-270. Griffiths PD, Baboonian C. Intrauterine transmission of cytomegalovirus in women known to be immune before conception. J Hyg (Camb) 1984;92:89-95. Nankervis GA, Kumar JL, Cox FE, Gold E. A prospective study of maternal cytomegalovirus infection and its effect on the fetus. AM j 0BSTET GYNECOL 1984; 149:435-40. Preece PM, Pearl KN, Peckham CS. Congenital cytomegalovirus infection. Arch Dis Child 1984;59: 1120-6. Rutter D, Griffiths P, Trompeter RS. Cytomegalic inclusion disease after recurrent maternal infection. Lancet 1985;2: 1182.
A complete list of references is available on request from the authors.