A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)

The George Washington University Biostatistics Center399 enrolled

Overview

Cytomegalovirus (CMV) is a common virus that usually presents with few if any side effects. When first infected, some people may have symptoms similar to mononucleosis (i.e., fatigue, weakness, fever, swollen glands). Most people in the United States are infected during childhood or as adults if they work around children. Pregnant women, who have not been infected with CMV in the past and become infected during pregnancy (i.e. a primary infection), may cause their babies to get infected with CMV. Babies that are infected may develop permanent disabilities including hearing loss and a small portion will die from the infection. Currently it is not routine practice to screen pregnant women for CMV infection. Additionally, there is no agreement about how to evaluate and manage pregnant women infected with CMV for the first time. There is also no evidence that treatment is beneficial for the baby. The purpose of this research study is to determine whether treating pregnant women who have a primary CMV infection with CMV antibodies will reduce the number of babies infected with CMV.

Cytomegalovirus (CMV) is the most common congenital infection, with approximately 44,000 congenitally infected infants in the U.S. per year. A substantial proportion of these 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 significantly reduce the rate of congenital CMV infection following maternal primary infection. The MFMU CMV Trial will address the primary research question: does maternal administration of CMV hyperimmune globulin lower the rate of congenital CMV infection among the offspring of women who have been diagnosed with primary CMV infection during early pregnancy? The research study is funded by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD). Sixteen medical centers across the country are participating in this research study. In all, 800 pregnant women who are identified with a primary CMV infection will be enrolled in this research study. The children of these women will be evaluated and tested at one and two years of age.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: FEMALEHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of primary maternal CMV infection on the basis of one of the following: 1. A positive CMV Immunoglobulin M (IgM) antibody and low-avidity maternal CMV Immunoglobulin G (IgG) antibody screen 2. Evidence of maternal seroconversion with development of CMV IgG antibody following a prior negative CMV screen * Gestational age at randomization no later than 23 weeks 6 days based on clinical information and evaluation of the earliest ultrasound; or no later than 27 weeks 6 days for women with a positive IgM, negative IgG initially screened before 23 weeks who are rescreened after 2-4 weeks and have evidence of IgG seroconversion. * Singleton pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14 weeks by project gestational age is acceptable. Exclusion Criteria: * 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. * Known hypersensitivity to plasma or plasma derived products * Planned termination of pregnancy * Known major fetal anomalies or demise * Maternal Immunoglobulin A (IgA) deficiency * Planned use of immune globulin, ganciclovir, or valganciclovir * 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) * Maternal immune impairment (e.g., HIV infection, organ transplant on anti-rejection medications) * 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 ascites). 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. * Positive fetal CMV findings from culture (amniotic fluid) or PCR. * Congenital infection with rubella, syphilis, varicella, parvovirus or toxoplasmosis diagnosed by serology and ultrasound or amniotic fluid testing. * Intention of the patient or of the managing obstetricians for the delivery to be outside a Maternal-Fetal Medicine Units Network (MFMU) Network center * Participation in another interventional study that influences fetal or neonatal death * Unwilling or unable to commit to 2 year follow-up of the infant

Locations (16)

University of Alabama - Birmingham

Birmingham, Alabama, United States

Stanford University

Stanford, California, United States

University of Colorado Denver

Aurora, Colorado, United States

Northwestern University

Chicago, Illinois, United States

Columbia University

New York, New York, United States

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Duke University

Durham, North Carolina, United States

Case Western Reserve-Metrohealth

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

...and 6 more locations

Outcomes

Primary Outcomes

Number of Participants With the Composite Primary Outcome

The primary outcome is a binary outcome defined by the occurrence or non-occurrence of any of the following vs. none of the following: fetal loss (spontaneous or termination), confirmed fetal CMV infection from amniocentesis, neonatal death before assessment of CMV infection can be made, or neonatal congenital CMV infection. Neonatal congenital CMV infection is diagnosed by urine or saliva collected by 3 weeks of age that is positive for CMV by culture (the intent will be to obtain in the first two days of life). In the event that Polymerase Chain Reaction (PCR) is positive but culture is negative, a repeat culture must be positive by 3 weeks of age.

Time frame: From randomization through 3 weeks of life

Number of Participants Who Had a Fetus or Neonate With CMV Infection

Component of composite primary outcome

Time frame: From randomization through 3 weeks of life

Number of Participants Who Had a Neonatal Death Without CMV Infection

component of composite primary outcome

Time frame: From randomization through 3 weeks of life

Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection

component of primary composite outcome

Time frame: From randomization through 3 weeks of life

Number of Participants With Fetal Death Without Proven CMV Infection

component of primary composite outcome

Time frame: From randomization through delivery

Secondary Outcomes

Number of Participants With Gestational Hypertension or Preeclampsia

Gestational hypertension or preeclampsia is a binary outcome defined by occurrence or non-occurrence of gestational hypertension or preeclampsia. Gestational hypertension or preeclampsia are new onset hypertension during pregnancy

Time frame: from randomization through discharge from the hospital

Number of Participants With Placental Abruption

Placental abruption is a binary outcome defined by occurrence or non-occurrence of placental abruption, defined as bleeding and contraction pain

Time frame: From randomization through delivery (maximum 42 weeks gestation)

Median Gestational Age at Delivery

Gestational age at delivery in weeks

Time frame: Delivery

Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks

Gestational age before 37 weeks gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 37 weeks gestation

Time frame: Delivery before 37 weeks gestation

Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days

Gestational age before 34 weeks, 0 days gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 34 weeks gestation

Time frame: Delivery before 34 weeks gestation

Number of Participants Reporting Yes or no to Medication Side Effects

Occurrence or non-occurrence of a designated side effect of medication

Time frame: From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation)

Number of Participants Who Had a Fetal or Neonatal Death

Fetal death or death of a neonate born alive

Time frame: From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) up to 120 days of life

Median Neonatal Head Circumference

Neonatal head circumference measured within 72 hours of birth

Time frame: 72 hours postpartum

Median Birth Weight

Birth weight as recorded in the medical record

Time frame: Delivery

Number of Participants With Fetal Growth Restriction

Fetal growth restriction is a binary outcome defined as the occurrence or non-occurrence of growth restriction (defined as \<5th percentile weight for gestational age, assessed specifically by sex and race of the infant based on United States birth certificate data)

Time frame: Delivery

Number of Participants With Symptomatic CMV Infection

Fetal or neonatal symptomatic CMV infection is a binary outcome defined as the occurrence or non-occurrence of symptomatic CMV infection defined as CMV isolated from an amniocentesis, or urine or saliva during the first three weeks of life and at least one of the following: jaundice (with direct bilirubin exceeding 20% of total bilirubin), thrombocytopenia , anemia , hepatitis, hepatomegaly, splenomegaly, growth restriction, failure to thrive, intracerebral calcifications, microcephaly, hypotonia, seizures, petechial rash, hearing loss, interstitial pneumonitis, thrombocytopenia, anemia, hepatitis, chorioretinitis, or CMV in cerebrospinal fluid

Time frame: During pregnancy up to 3 weeks postpartum

Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) as determined by cranial ultrasounds performed as part of routine clinical care and classified based on the Papile classification system. IVH is a binary outcome defined by occurrence or non-occurrence of IVH