Passive Immunization During Pregnancy for CMV
Passive Immunization During Pregnancy for CMV
Abstract & Commentary
By Hal B. Jenson, MD, FAAP, Chair, Department of Pediatrics, Director, Center for Pediatric Research, Eastern Virginia Medical School and Children’s Hospital of the King’s Daughters, Norfolk, is Associate Editor for Infectious Disease Alert.
Dr. Jenson is on the speaker’s bureau for Merck.
Synopsis: A non-randomized study of hyperimmune globulin for pregnant women with primary cytomegalovirus infection showed that it is safe and may be effective in the treatment and prevention of congenital CMV infection.
Source: Nigro G, et al. Passive Immunization During Pregnancy For Congenital Cytomegalovirus Infection. N Engl J Med. 2005;353:1350-1362.
A prospective, non-randomized, non-controlled trial was performed from 1995-2003 at 8 cities in Italy. Pregnant women with primary cytomegalovirus (CMV) infection during, or a few months before, pregnancy were identified by seroconversion, including 148 asymptomatic women, 8 symptomatic women with an acute illness, and 1 asymptomatic woman with fetal abnormalities on ultrasonography. Primary CMV infection was confirmed by seroconversion in 131 women, and by CMV-specific IgM antibodies in 26 women who also had increasing titers of CMV-specific IgG antibodies.
The treatment group consisted of women with primary CMV infection more than 6 weeks before enrollment who underwent amniocentesis as soon as safely feasible. Of these 79 women, 24 had no evidence of CMV in amniotic fluid, and were followed as a comparison group. The other 55 women had CMV-positive amniotic fluid by culture or PCR for CMV DNA, and were offered treatment with a single dose of intravenous hyperimmune globulin 200 U/kg of maternal weight. Of the 55 women, 31 received hyperimmune globulin, 14 declined, and 10 had an elective abortion. One or two additional doses, 2 to 6 weeks apart, of intra-umbilical-cord or intra-amniotic hyperimmune globulin 400 U/kg of fetal weight were administered in 9 women with ultrasonographic evidence of persistent fetal involvement.
In the treatment group, only 1 of 31 (3%) women who received hyperimmune globulin gave birth to an infant with congenital CMV disease, compared to 7 of 14 (50%) women who did not receive hyperimmune globulin. There was a significantly lower risk of congenital CMV disease among women receiving hyperimmune globulin (adjusted odds ratio, 0.02; 95% CI, 0.15; P < 0.001).
The prevention group consisted of women with primary CMV infection who did not undergo amniocentesis. Reasons included infection within 6 weeks before enrollment, gestation less than 20 weeks (making detection of CMV in amniotic fluid unlikely), or declining the procedure. These women were offered intravenous hyperimmune globulin 100 U/kg every month until delivery. Of these 102 women, 37 received immune globulin and gave birth to 37 newborns. Of the other 65 women who declined immune globulin, 47 gave birth and 18 had an elective abortion.
In the prevention group, only 6 of 37 (16%) women who received hyperimmune globulin gave birth to an infant with congenital CMV disease, compared to 19 of 47 (40%) women who did not receive hyperimmune globulin. There was a significantly lower risk of congenital CMV disease among women receiving hyperimmune globulin (adjusted odds ratio, 0.32; 95% CI, 0.10 to 0.94; P = 0.04).
The number and percentage of immune cells were measured at enrollment and about 8 weeks later in 26 women receiving hyperimmune globulin and 21 untreated women. Women who received hyperimmune globulin had an approximately 33% decrease in total natural killer cells and activity and HLA-DR+ cells, and an approximately 40% decrease in absolute number of natural killer cells and HLA-DR+ cells.
The CMV hyperimmune globulin was Cytotect Biotest, with a mean titer of anti-CMV IgG of 1:409,600. No adverse effects of hyperimmune globulin were observed.
Commentary
CMV is the most common cause of congenital infection, occurring in approximately 1% of all newborns. About 10-20% of infected newborns are symptomatic at birth, and neurologic deficits—especially sensorineural hearing loss—occurs in 8-13% of newborns with asymptomatic infection. CMV may be the most significant cause of hearing loss.
The results of this study are provocative because they substantiate a safe and effective method for preventing congenital CMV infection. This effect is similar to the effect of passive immunization on other perinatal pathogens, including hepatitis B virus and varicella-zoster virus. The reduction in risk is not absolute, as this study confirms. This is also consistent with the greatly reduced—but not absent—risk of congenital CMV infection among women with reactivated CMV infection during pregnancy. This is similar to the situation with perinatal herpes simplex virus infection.
Treatment with hyperimmune globulin decreased both the number and percentage of natural killer cells and HLA-DR+ cells, both of which are increased at the onset of CMV infection. High levels of these cells are associated with high levels of cytokines such as tumor necrosis factor- (TNF-), which may contribute to fetal damage. Hyperimmune globulin may reduce the incidence of congenital CMV disease by virus neutrallization, or possibly by immunomodulatory effects.
Despite these interesting and promising results, the logistical aspects associated with implementing a scheme for administration of hyperimmune globulin to pregnant women with primary CMV infection are immense. Perhaps the critical message is that antibodies to CMV are protective for congenital CMV infection, which underscores the opportunity and need to develop an effective CMV vaccine to prevent perinatal CMV infection.
A prospective, non-randomized, non-controlled trial was performed from 1995-2003 at 8 cities in Italy. Pregnant women with primary cytomegalovirus (CMV) infection during, or a few months before, pregnancy were identified by seroconversion, including 148 asymptomatic women, 8 symptomatic women with an acute illness, and 1 asymptomatic woman with fetal abnormalities on ultrasonography.Subscribe Now for Access
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