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.

Immunoprophylaxis against cytomegalovirus disease.

Patients with either deficient or immature immune systems need protection against cytomegalovirus (CMV) disease. That maternal immunization prior to pregnancy will protect newborns from congenital disease is suggested by the fact that newborns who acquire CMV either via transfusion or transplacentally are relatively protected if their mothers had antibodies to CMV prior to pregnancy. For patients becoming partially immunocompromised following solid organ transplantation, protection against severe CMV disease is afforded by immunity acquired either by wild-type infection prior to transplantation or passive or active immunization. In three randomized placebo-controlled studies, live attenuated CMV vaccine has successfully protected seronegative recipients of kidneys from seropositive donors from severe CMV disease by efficiently inducing humoral and cellular immunity. Subunit vaccines comprised of glycoprotein gB, the viral component containing the majority of viral neutralizing epitopes, are in the early phases of study, as are strategies to provide patients with CD8+ deficiency immunoprophylaxis via adoptive transfer of cytotoxic T-cells expanded in vitro against CMV structural proteins. Given all of these facts, safe and effective CMV immunoprophylaxis against CMV disease is possible.

Molecular epidemiology of cytomegalovirus: evidence for viral transmission to parents from children infected at a day care center.

Based on an analysis of the DNA of 16 cytomegalovirus (CMV) isolates obtained from children attending a day care center, we had previously determined that one group of 7 and another group of 4 children were shedding common viral strains. Because the DNA of each epidemiologically unrelated strain of CMV is unique, at least 9 of these 11 children acquired CMV from other children attending the day care center. In order to assess CMV transmission between these 11 viruric children and their parents, the parents were surveyed for CMV infections. Nine of the 10 mothers of the viruric children were seropositive but only 12 of 33 mothers of nonviruric children at the day center were seropositive (P less than 0.007), Fisher's exact test). Urine and saliva specimens from each parent of the viruric children were cultured for CMV. Three parents (a father and two pregnant mothers) were excreting virus. When analyzed with restriction endonucleases, the viral DNA of the isolate from each parent was identical to that from the virus excreted by the child and from the virus excreted by other children at the day care center. The results of this survey indicate that CMV was frequently transmitted to parents from children who had acquired the virus at 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 pregnancy.

Cytomegalovirus remains the most common congenital infection worldwide, with approximately 1% of all newborns infected in utero. Of those infected in utero, approximately 10% will have signs and symptoms of cytomegalovirus infection at birth and develop sequelae, especially mental retardation, hearing deficit, or both. Recent data indicate that more than 90% of symptomatic infections or infections causing sequelae occur following a primary maternal infection during pregnancy. The overall risk of delivering an infant who will develop significant handicaps following a primary maternal infection is between 10% and 20%. Between 1% and 2% of seronegative women may acquire a primary cytomegalovirus infection during pregnancy, but seronegative women at high risk include day-care workers, who have a 10% to 20% annual infection rate, and the seronegative mothers of infected children under 2 years of age, 50% of whom will acquire cytomegalovirus annually from their children. Adolescents are another group who may have a high infection rate during pregnancy. Although a cytomegalovirus vaccine is still many years from introduction, these observations strengthen the need and feasibility for a cytomegalovirus vaccine. Pending vaccine development and evaluation, several possible strategies for intervention to prevent primary infection for high-risk pregnancies are suggested.