Maternal Factors Predictive for Fetal Cytomegalovirus Infection

Maternal viremia predicted fetal infection and neonatal outcome of infants of women with a primary cytomegalovirus (CMV) infection during pregnancy, according to study results published in Clinical Infectious Diseases.

To determine factors predictive of infant outcome, researchers analyzed a large registry database of 304 pregnant women with primary CMV who were enrolled between 2010 and 2017. These women delivered 281 infants, among whom 108 had CMV infection. A total of 157 women in the study population had been treated with an average of 2 doses (range 1 to 6) of high-dose hyperimmune globulin (200 mg/kg/infusion). Long-term follow-up at age 4 years (range 1 to 8 years) was conducted for 173 infants without CMV infection and 106 with CMV

Regression models tested 31 covariates and found 4 factors that predicted fetal infection:

• A1.8-fold increase (30% vs 56%) in the rate of congenital infection without treatment with hyperimmune globulin (P< .0001, adjusted odd ratio [aOR] =5.2)
• A 1.8-fold increase (32% vs 56%) in maternal viral DNAemia prior to hyperimmune globulin administration (P= .002, aOR=3.0)
• Abnormal ultrasounds (P= .0002, aOR=54.2)
• Diagnosis of maternal infection via seroconversion rather than avidity (P= .007, aOR=3.3)

Lack of hyperimmune globulin and abnormal ultrasounds (P= .001) predicted symptoms. Three factors predicted long-term sequelae:

• Not receiving hyperimmune globulin (P= .001, aOR= 13.2)
• Maternal infection in early gestation (P= .017, OR = 0.9)
• Abnormal ultrasounds (P< .003, OR =7.6)

The results also showed that, after hyperimmune globulin therapy, prevalence and copy/number of DNAemia declined.

The investigators also highlighted several important factors that were unassociated with fetal infection, symptoms, or disease. These included viremia after the first test; the number of doses of hyperimmune globulin; the interval between maternal infection and DNA testing, hyperimmune globulin administration, and the duration and resolution of viremia; and the copy numbers of DNA in maternal blood and/or amniotic fluid.

The study was limited by potential selection bias and the lack of an appropriate placebo. However, according to investigators, this study “has implications for the design of placebo controlled randomized trials.” The researchers explained that the optimal dose of hyperimmune globulin and monoclonal antibodies is based on the half-life of CMV-specific antibodies rather than that of other immunoglobulin G molecules in preparations. Moreover, they argued that enrollment using low avidity is unacceptable due to difficulties in accurately estimating the time of maternal infection and consequently accurate rates of mother-fetal transmission. The researchers also noted that either active or passive immunotherapy is optimal when used in early gestation, and maternal viremia should be monitored during clinical trials in order to avoid introducing selection bias. Finally, the researchers suggested that data from ultrasound and magnetic resonance examinations are “a very appropriate endpoint for clinical trials of active or passive immunization.”

Investigators concluded that, while no randomized trial has demonstrated a benefit of CMV hyperimmune globulin on infant outcomes, these findings suggest that maternal CMV hyperimmune globulin therapy may be of benefit. Further clinical research is required. The data may also be useful for patient counseling and support the efficacy of high-dose hyperimmune globulin to prevent fetal infection, neonatal symptoms, and long-term disabilities.

Reference

Nigro G and Adler SP. High-dose CMV hyperimmune globulin (HIG) and maternal CMV DNAemia independently predict infant outcome in pregnant women with a primary cytomegalovirus (CMV) infection [published online October 20 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz1030