CMV

Overview

Status: Recruiting
Keywords: Pregnant , Cytomegalovirus , CMV , Infection in pregnancy
IRB Number: 00053808
Specialty: Maternal-Fetal Medicine
Sub Specialties:

Brief Summary

Cytomegalovirus (CMV) is the most common congenital infection, with a prevalence of approximately 1% in the United States, translating into 44,000 congenitally infected infants per year. A substantial proportion of these 44,000 infants will die or suffer permanent injury as a result of their infection. The severity of congenital infection is greatest with primary maternal CMV infection. Currently, there is no proven method of preventing congenital CMV infection, and the approach to primary maternal CMV infection in the United States is haphazard and ineffective. One small, non-randomized study suggests that maternal administration of CMV hyperimmune globulin may reduce the rate of congenital CMV infection following maternal primary infection. We propose to screen gravidas in the first half of pregnancy for recent primary CMV infection, and evaluate in a proper randomized clinical trial whether maternal administration of CMV hyperimmune globulin will prevent congenital CMV infection.
 
We hypothesize that maternal administration of CMV hyperimmune globulin will lower the rate of congenital CMV infection among the offspring of women who have been diagnosed with primary CMV infection during early pregnancy.

Study Abstract

Cytomegalovirus (CMV) is the most common congenital infection, with a prevalence of approximately 1% in the United States, translating into 44,000 congenitally infected infants per year.  A substantial proportion of these 44,000 infants will die or suffer permanent injury as a result of their infection. The severity of congenital infection is greatest with primary maternal CMV infection. Currently, there is no proven method of preventing congenital CMV infection, and the approach to primary maternal CMV infection in the United States is haphazard and ineffective. One small, non-randomized study suggests that maternal administration of CMV hyperimmune globulin may reduce the rate of congenital CMV infection following maternal primary infection.  We propose to screen gravidas in the first half of pregnancy for recent primary CMV infection, and evaluate in a proper randomized clinical trial whether maternal administration of CMV hyperimmune globulin will prevent congenital CMV infection.  

Primary Hypothesis

Maternal administration of CMV hyperimmune globulin will lower the rate of congenital CMV infection among the offspring of women who have been diagnosed with primary CMV infection during early pregnancy.

Principal Investigator: Michael Varner
Department: Maternal-Fetal Medicine
Co Investigator:

Contact Information

Name:Kim Hill
Phone: 801-585-5499
Email: kim.hill@hsc.utah.edu

Inclusion Criteria

1.Diagnosis of primary maternal CMV infection is defined as one of the following:
 
a.A positive CMV IgM antibody (≥ 1.00 Index) and low-avidity maternal CMV IgG antibody screen (< 50.0%)
 
b.Evidence of maternal seroconversion with development of CMV IgG antibody (≥ 6.0 AU/ml) following a prior negative CMV screen (< 6.0 AU/ml)
 
The CMV IgG, IgM, and IgG avidity are measured on the Abbott Architect system. The sensitivities and specificities for the three assays range from 97-100%. The IgG avidity which determines a primary infection has a specificity of 100%. The avidity assay has also been shown to correlate much more highly with congenital CMV infection, than using IgM alone and is comparable to seroconversion seen with serial maternal CMV IgG titers.
 
2.Gestational age at randomization no later than 23 weeks based on clinical information and evaluation of the earliest ultrasound as described in “Gestational Age Determination” stated below; or 

3.Gestational age at randomization  no later than 276 weeks for the following:

  • Women with a positive IgM and negative IgG, initially screened before 23 weeks who are rescreened after 2 weeks and have evidence of IgG seroconversion
  • Women with initially negative IgM and negative IgG, rescreened after 8 weeks with evidence of seroconversion before 23 weeks

4. Randomization must occur within six weeks of the blood draw for the qualifying screening sample.

5.Singleton pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14 weeks by project gestational age (see below) is acceptable.
 

Gestational Age Determination
 
Gestational age is determined in the following manner, and is denoted “project gestational age”. The “project EDC”, which is based on the project gestational age, cannot be revised once a determination has been made. In the case of in-vitro fertilization, project gestational age is calculated from the date of embryo transfer and the embryo age at transfer.
 
1.The first day of the last menstrual period (LMP) is determined, and a judgment made as to whether or not the patient has a “sure” LMP date.
 
2.If the LMP date is unsure, the ultrasound measurements obtained at the patient’s first dating ultrasound examination are used to determine the project gestational age, by the standard method of ultrasound gestational age determination at that institution.
 
3.If the LMP date is sure, project gestational age is determined by a comparison between the gestational age by LMP and by the earliest dating ultrasound.
 
•If the earliest dating ultrasound confirms the gestational age by LMP within the number of days specified in
 
•Table 1 below, the LMP-derived gestational age is used to determine the project gestational age.
 
•If the ultrasound determined gestational age does not confirm the LMP generated gestational age within the number of days specified in
 
•Table 1, the ultrasound is used to determine the project gestational age.
 

 
Table 1. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP
 

 
Gestational age at first Ultrasound agreement with LMP
 
ultrasound by LMP
 
up to 19 weeks ± 7 days
 
20 weeks to 29 weeks ± 14 days
 
30 weeks or more ± 21 days
 

 

Exclusion Criteria

1.Maternal CMV infection pre-dating pregnancy as defined by a high IgG avidity index or a positive IgG in the presence of a negative IgM.
 
2.Known hypersensitivity to plasma or plasma derived products
 
3.Planned termination of pregnancy
 
4.Known major fetal anomalies or demise
 
5.Maternal IgA deficiency, because of the potential for developing antibodies to IgA and the chance of a maternal anaphylactic reaction to subsequent administration of blood products containing IgA, including Cytogam®.
 
6.Planned use of immune globulin, ganciclovir, or valganciclovir
 
7.Maternal renal disease (most recent pre-randomization serum creatinine ≥ 1.4 mg/dL; all women must have serum creatinine measured during the pregnancy and prior to randomization), because IV immune globulin products have been reported to be associated with renal dysfunction.
 
8.Maternal immune impairment (e.g., HIV infection, organ transplant on anti-rejection medications), because this may require use of IV immune globulin products
 
9.Findings on pre-randomization ultrasound suggestive of established fetal CMV infection (cerebral ventriculomegaly, microcephaly, cerebral or intra-abdominal calcifications, abnormalities of amniotic fluid volume, echogenic bowel or ascities). Abnormally low amniotic fluid volume is defined as no fluid prior to 14 weeks or maximum vertical pocket < 2 cm on or after 14 weeks gestation. Abnormally high amniotic fluid volume is defined as > 10 cm.
 
10.Positive fetal CMV findings from culture (amniotic fluid) or PCR.
 
11.Congenital infection with rubella, syphilis, varicella, parvovirus or toxoplasmosis diagnosed by serology and ultrasound or amniotic fluid testing.
 
12.Intention of the patient or of the managing obstetricians for the delivery to be outside a MFMU Network center, unless protocol subcommittee approval is obtained for that specific delivery location, which will be conditional on special provisions being made to ensure collection of samples to determine the primary outcome, and IRB approval at the delivery hospital.
 
13.Participation in another interventional study that influences fetal or neonatal morbidity/mortality or developmental outcome
  
14.Unwilling or unable to commit to 2 year follow-up of the infant