Prevention of maternal-fetal transmission of cytomegalovirus after primary maternal infection in the first trimester by biweekly hyperimmunoglobulin administration.

OBJECTIVE: To examine the efficacy of biweekly hyperimmunoglobulin (HIG) administration to prevent maternal-fetal transmission of cytomegalovirus (CMV) in women with primary first-trimester CMV infection. METHODS: This was a prospective observational study of women with confirmed primary CMV infection in the first trimester who had the first HIG administration at or before 14 weeks' gestation. All women had biweekly HIG treatment until 20 weeks' gestation at a dose of 200 IU/kg of maternal body weight. Each subject underwent amniocentesis at least 6 weeks after first presentation at about 20 weeks. Primary outcome was maternal-fetal transmission at the time of amniocentesis, and secondary outcome was the frequency of congenital CMV infection at birth. The results were compared with a historic cohort of women with first-trimester CMV infection who did not undergo HIG treatment and who had amniocentesis at about 20 weeks. RESULTS: Subjects were 40 pregnant women with a primary CMV infection, with a median gestational age at first presentation of 9.6 (range, 5.1-14.3) weeks. On average, HIG administration started at 11.1 weeks and continued until 16.6 weeks. Within this interval, HIG was administered between two and six times in each patient. While CMV immunoglobulin-G (IgG) monitoring showed periodic fluctuations during biweekly HIG administration cycles, high CMV-IgG avidity indices remained stable over the whole treatment period. Maternal-fetal transmission before amniocentesis occurred in only one of the 40 cases (2.5% (95% CI, 0-13.2%)). At delivery, two additional subjects were found to have had late-gestation transmission. Considering all three cases with maternal-fetal transmission, the transmission rate was 7.5% (95% CI, 1.6-20.4%) in our 40 cases. All infected neonates were asymptomatic at birth. The matched historical control group consisted of 108 pregnancies. Thirty-eight transmissions (35.2% (95% CI, 26.2-45.0%)) occurred in the control group, which was significantly higher (P < 0.0001) than the transmission rate in the HIG treatment group. CONCLUSION: After a primary maternal CMV infection in the first trimester, biweekly HIG administration at a dose of 200 IU/kg prevents maternal-fetal transmission up to 20 weeks' gestation. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Molecular epidemiology of cytomegalovirus: a study of factors affecting transmission among children at three day-care centers.

To account for the wide variations in the prevalence of cytomegalovirus infections among day-care centers we serially tested 309 children at three day-care centers for 3 years. Based on the DNA restriction endonuclease pattern of each isolate, the rate of infection for children differed significantly (P less than 0.001) among centers: at Center 1, 50% (46 of 93) of children acquired cytomegalovirus in day care; at Center 2, 62% (64 of 104); and at Center 3, 25% (21 of 84). Infection rates were associated with the number of infants enrolled, and half or more of infected children were younger than 24 months of age. Six of 7 new isolates were introduced by children 18 months of age. Based on DNA patterns the prevalent isolates at Centers 1 and 2, although different, were shed for an average of 22 and 23 months, respectively, compared with an average of 15 months for other isolates (P less than 0.001). Reinfections with the prevalent isolates were observed for 2 of 34 children tested. The most important factors affecting day-care center transmission are the number of infants enrolled and prolonged viral shedding, possibly enhanced by reinfection.

Cytomegalovirus and child day care: risk factors for maternal infection.

To determine the rates and factors affecting cytomegalovirus transmission from children infected in day care to their seronegative mothers, we prospectively monitored 96 seronegative mothers. Of 46 seronegative mothers without infected children, 2 seroconverted. Among 50 mothers with infected children, 19 seroconverted and of these 19, 9 shed cytomegalovirus and all 9 shed the same isolate as their child. The annual seroconversion rate for these women was 30%, significantly higher than the 3% rate for mothers without infected children (P less than 0.001; relative risk, 10.2; 95% confidence interval, 2.4, 43.8). Maternal infection was not associated with maternal age, race, duration of observation, duration of viral shedding by their children or the DNA pattern of each isolate but was associated with the age when a child's infection was identified. Only 3 of the 19 mothers who seroconverted had children older than 20 months of age (26, 28 and 28 months). Sixteen (57%) of 28 mothers with infected children 20 months of age or younger became infected compared with only 3 (13%) of 22 mothers with infected children more than 20 months (P less than 0.007), Fisher's exact test, two tailed; relative risk, 3.9; 95% confidence interval, 1.3, 11.8). For mothers with infected children younger than 20 months of age the interval between identification of her child's infection and maternal infection ranged from 1 to 26 months (8 +/- 6 (SD) months). Survival estimates revealed that mothers of infected children younger than 20 months of age acquired cytomegalovirus significantly more rapidly than mothers of older children (chi square, 9.34; P less than 0.0022).

Human parvovirus B19 infections in women of childbearing age and within families.

Human parvovirus B19 (B19) crosses the placenta causing fetal death. We used an indirect capture enzyme immunoassay to measure IgG to B19 in sera of 845 subjects from 2 groups. The first group included 405 women (mean age, 30 years) composed of 85 pediatric nurses and 130 other female hospital employees, 122 women employed caring for preschool children and 68 mothers of preschool children enrolled in day care. Twenty-eight percent of all these women were seropositive. Seropositivity was unrelated to occupational group. Four of 235 women observed between 1983 and 1987 for a mean of 435 days/woman acquired B19 infections (an annual seroconversion rate of 1.5%). We investigated intrafamilial associations of B19 infection in a second group of 440 subjects from 111 families. Seropositivity of parents was not associated with seropositivity of their children. Seropositivity of one spouse was not associated with seropositivity of the cospouse. However, of 47 seropositive older siblings, 32 (68%) of their younger siblings were seropositive, compared to 20 (18%) seropositive younger siblings of 112 seronegative older siblings (P less than 0.001). B19 infections increased with age from 19% for those younger than 10 years to 67% for those older than 49 years. For all ages females had a higher rate (51%) of B19 infection than males (38%). These data suggest that children may be more susceptible to B19 than adults and B19 infections occur infrequently among women younger than 40 years of age. However, during local outbreaks the B19 infection rate for susceptible pregnant women remains unknown.

Intrauterine parvovirus B19 infection may cause an asymptomatic or recurrent postnatal infection.

Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true incidence of intrauterine infection is unknown. For 19 women with serologically confirmed B19 infections between 4 and 38 weeks of gestation, we performed follow-up examinations of their infants. Serial sonograms of the 19 fetuses showed that none developed hydrops. All 19 women delivered healthy term infants. Cord sera of four infants were tested for IgM to B19 and three were positive. Between 3 and 21 months of age, all 19 infants had normal physical examinations, developmental evaluations and hematocrits; and 16 lacked IgG to B19. One infant who was IgM-positive to B19 at birth was IgM-positive at age 7 months when he also had an IgG titer to B19 of 1:500,000 (mother's concurrent titer, 1:10,000), and had B19 DNA in serum detected by polymerase chain reaction. The other two infants who were IgM-positive at birth were IgM- and IgG-negative by 11 and 16 months of age. These results suggest that intrauterine B19 infection may be frequent and occasionally cause an asymptomatic postnatal infection.

Serologic and virologic evidence for frequent intrauterine transmission of human parvovirus B19 with a primary maternal infection during pregnancy.

OBJECTIVE: To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infection and identify factors that may influence this rate. METHODS: Forty-three pregnant women at two medical centers were identified with a primary B19 infection and followed to delivery. At delivery maternal and infant (umbilical cord) blood was obtained for B19 serologic and virologic PCR testing. RESULTS: All of the women delivered healthy infants at term and none was hydropic. Overall 22 (51%) of the 43 infants had some evidence of a congenital B19 infection. B19-specific IgM was detected in 11 infants at delivery, B19 IgA was detected in 10 and B19 DNA was detectable by PCR in 11 infants. One infant was negative at birth but became positive for IgM, IgA and PCR at 6 weeks of age. No association was found between the likelihood of intrauterine infection and: maternal age; symptomatic maternal infection; method of delivery; maternal IgG titer at delivery; maternal IgG avidity at delivery; or maternal viremia at delivery. Intrauterine infection was associated with maternal IgM positivity at delivery; this association may have been a result of maternal infection occurring later in gestation. CONCLUSION: Although the incidence of intrauterine hydrops and fetal demise after maternal infection is low, there is a high rate of intrauterine viral infection that occurs throughout gestation and yields newborns who, although infected in utero, are asymptomatic at birth.

Prevention of child-to-mother transmission of cytomegalovirus by changing behaviors: a randomized controlled trial.

BACKGROUND: To determine whether a behavioral prevention approach reduces child-to-parent transmission of cytomegalovirus. METHODS: Subjects were seronegative mothers whose child was less than 36 months of age and was shedding cytomegalovirus. Nonpregnant women were randomly assigned to three groups. Mothers in the education group (E) were given instructions about protective behaviors (frequent hand washing, wearing latex gloves) and risky behaviors to avoid (intimate contact with the child). Disposable diapers, liquid soap and latex gloves were provided. During biweekly home visits glove and soap use were monitored for an indirect objective measure of adherence to the protective behaviors. Throughout the study mothers self-reported the frequency they engaged in protective and risky behaviors. In addition to the procedures for Group E the adherence and education group (A) also received social reinforcement for adherence and problem solving for any perceived problems with the behavioral recommendations. The control group (C) received no intervention. A fourth group of pregnant women received an intervention equivalent to that of the education group. RESULTS: Eight of 17 women in Group C and 4 of 11 women in Group E seroconverted. For both E and Group C the average time from enrollment to infection was 4 months (range, 2 to 7 months). Two of 8 women in Group A seroconverted (1 at 3 months and 1 at 8 months). None of 14 pregnant women observed for an average of 8.4 months during pregnancy seroconverted. CONCLUSIONS: These results suggest that intervention for pregnant women is effective because pregnant women will perceive a higher risk and be more motivated to adhere to recommendations than nonpregnant women.

Safety and immunogenicity of the Towne strain cytomegalovirus vaccine.

BACKGROUND: Women with naturally acquired serum antibodies to cytomegalovirus (CMV) are usually protected against both frequent secondary infection and giving birth to infants severely affected by intrauterine CMV infection. OBJECTIVE: To determine the feasibility of using a live attenuated strain of CMV (Towne) to achieve immunity similar to that provided by wild-type infection, we evaluated a new lot of the Towne strain of CMV in 3 open label trials involving 68 men, 63 women of childbearing age and 13 children, respectively. RESULTS: Mild local reactions occurred among approximately one-third of subjects. There were no systemic reactions. All 45 subjects tested developed lymphoproliferative responses to CMV. CD8+ class I-restricted cytotoxic T cell responses specific for CMV antigens were detected in three of four subjects and persisted for 6 months. Neutralizing titers were maximal at 2 to 4 months postimmunization, were dose-dependent and were comparable to those induced by natural infection. CONCLUSION: These results support further evaluation of the Towne strain of CMV in women at risk for acquiring CMV infection during pregnancy or among children transmitting CMV to pregnant women.

Prospective evaluation of 618 pregnant women exposed to parvovirus B19: risks and symptoms.

OBJECTIVE: To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the fetal morbidity of those infections. METHODS: We obtained demographic and occupational information about pregnant women exposed to sources of B19 and about the nature and duration of the exposures. We performed serologic testing 10-14 days after exposure using an indirect capture enzyme-linked immunosorbent assay. Women with immunoglobulin (Ig) M were examined with weekly ultrasound until 12 weeks after exposure, and the outcome of the pregnancy was ascertained from interviews with patients and their obstetricians. Logistic regression analysis was used to determine risk factors for maternal immunity and infection by B19. RESULTS: Of 618 pregnant women exposed, 307 (49.7%) were immune to B19, 259 remained susceptible after exposure, and 52 (16.7% of all susceptibles) contracted B19 infection. None of the 52 fetuses of infected women developed nonimmune hydrops, and there were no fetal deaths attributable to B19 in this group. The relative risk of maternal B19 infection was 2.8 if the source was a related child living in the household (95% confidence interval 1.7, 4.6; P < .001). No significant differences were found for maternal B19 infection in eight categories of maternal occupation. Maternal symptoms of polyarthralgia (46%), fever (19%), and nonspecific rash (38%) were significantly more common (P < .001) in IgM-positive patients than in noninfected women (4.1%, 2.8%, and 5.7%, respectively). Only 17 (33%) of the IgM-positive women were entirely asymptomatic. CONCLUSION: The risk of maternal B19 infection in pregnancy could not be predicted by a gravida's occupation, but it was significantly higher when the source of exposure was her own child. The fetal risk of nonimmune hydrops after maternal B19 infection must be very low. As a consequence, exclusion of pregnant women from the workplace during endemic periods with seasonal clusters of cases is not justified. Weekly fetal ultrasound evaluation in these cases carries a low yield.

Culture confirmation of cytomegalovirus and herpes simplex virus by direct enzyme-labeled DNA probes and in situ hybridization.

Using probes consisting of horseradish peroxidase (HRP) directly attached to DNA, scrapings or trypsinized cells from 217 adequate clinical samples were cultured and analyzed in 3 blind studies by in situ hybridization for the presence of cytomegalovirus (CMV) and herpes simplex virus (HSV). Sixty samples were judged inadequate due to insufficient cell numbers; however, this problem was significantly decreased during the course of the study. One hundred and eighteen samples were found positive and 70 samples were found negative for CMV. Scrapings of cultured cells from 29 clinical samples revealed 9 samples which were positive and 20 samples which were negative for HSV. Forty-two additional samples, containing either uninfected cells or cells infected with various strains of CMV, were analyzed for the ability of the HRP-DNA CMV probe to detect such isolates. Twenty samples were positive and 22 negative for CMV. No false-negatives or false-positives were observed for either CMV or HSV. In addition to the specificity noted above neither the CMV nor the HSV DNA probe hybridized to potential contaminants found in clinical specimens.

Changing protective and risky behaviors to prevent child-to-parent transmission of cytomegalovirus.

Child-to-parent transmission of cytomegalovirus may be reduced by increasing protective behaviors (handwashing and glove use) and decreasing risky behaviors (intimate contact between child and parent). This study showed that an educational intervention resulted in increases in reported and objective measures of protective behaviors and decreases in reported risky behaviors. Further study must determine if changes in protective and risky behavior are maintained and prevent cytomegalovirus transmission.

Molecular epidemiology of cytomegalovirus: viral transmission among children attending a day care center, their parents, and caretakers.

This 26-month prospective study monitored 104 children from one day care center (DCC), and their families, for cytomegalovirus (CMV) infections. Among the children, 14 different strains of CMV were identified by restriction endonuclease analysis of the viral DNA of isolates. Three of these strains infected 44 DCC children and apparently were transmitted within the DCC environment. Only children younger than 3 years of age acquired the DCC-associated CMV strains. Of 75 seronegative children in this age group, 34 acquired DCC-associated CMV strains, and four were infected with unique strains. Among 23 children older than 3 years of age, none acquired the DCC-associated strains, although six were infected with unique strains. Of 18 seronegative mothers, six acquired CMV infections within 3 to 7 months after their children became infected; the strains were identical to those isolated from their children and were DCC associated. Four fathers, three seropositive mothers, and two caretakers also shed DCC-associated strains of CMV. None of the 31 mothers whose children were not infected shed CMV. There was no apparent CMV-associated morbidity. These results prove the frequent transmission of CMV within the DCC environment and from DCC children to their parents. They further suggest that caretakers do acquire CMV from DCC children.

The molecular epidemiology of cytomegalovirus transmission among children attending a day care center.

Cytomegalovirus (CMV) viruria was detected in 16 (25%) of 66 children attending a day care center. A significantly lower prevalence (6.9%) of viruria occurred among an age-matched control group of 1,457 hospitalized children. CMV DNA was compared by restriction endonuclease digestion of cell-associated CMV DNA, prepared by the Hirt procedure. CMV DNA fragments were detected directly on agarose gels by a 2-hr in situ hybridization with 32P-labeled DNA plasmids containing XbaI fragments of the Towne strain. EcoRI digestion of DNA isolated from 11 hospitalized children revealed 11 unique strains. A similar analysis, with EcoRI and several other endonucleases, of DNA isolated from the urine of 16 children attending the day care center revealed that one group of seven children and another group of four children were excreting identical strains of CMV. All seven children in the first group were less than 29 months old; six of these children shared the same classroom. All four children in the second group were greater than 36 months old; three were assigned to the same room. These results prove that CMV was frequently transmitted among children attending the day care center.

Neonatal cytomegalovirus infections due to blood.

Infants with very low birthweights (less than 1250g) are immunocompromised and have immature hematopoietic systems. They require frequent blood transfusions and have an increased susceptibility to infection. These very low birthweight infants who lack passively acquired antibody against CMV, acquire transfusion-associated CMV infections with a frequency of approximately 30%. These infections are associated with significant morbidity and mortality. The source of these postnatally acquired CMV infections are seropositive blood donors. These infections can be prevented by appropriate donor selection and/or blood processing. Recent but limited data suggests that all infants (regardless of birthweight or the presence of antibody against CMV) should receive CMV seronegative blood products if they are likely to receive multiple transfusions from multiple donors.

Cytomegalovirus and child day care. Evidence for an increased infection rate among day-care workers.

To determine whether day-care workers acquire cytomegalovirus infection from the children they care for, we studied 610 women employed at 34 day-care centers over two years. Forty-one percent of the caretakers were seropositive for cytomegalovirus. After adjustment for the effects of race, marital status, and age on seropositivity, the women who cared for children younger than two years of age had a significantly higher seropositivity rate (46 percent) than the women who cared for children older than two years of age (35 percent) (relative risk, 1.29; 95 percent confidence interval, 1.05 to 1.57; P less than 0.02). Of 202 initially seronegative caretakers (observed for an average of 305 days per woman), 19 seroconverted, for an annual seroconversion rate of 11 percent. This rate was significantly higher than the 2 percent annual rate of seroconversion among 229 seronegative women (11 of whom seroconverted) in a comparison group of female hospital employees observed for an average of 781 days per woman (relative risk, 5.0; 95 percent confidence interval, 2.4 to 10.5; P less than 0.001). At three day-care centers in which the children were also studied, seven of the nine women shed isolates of cytomegalovirus in their saliva or urine that had EcoRI and BamHI DNA-digestion patterns identical to the DNA patterns of isolates shed by one or more children in their care. We conclude that workers in day-care centers may acquire cytomegalovirus infection from the children in their care and that this risk is significantly greater among those who care for children less than two years of age.