A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV) (CMV)

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.

Study Overview

• Status: Completed
• Conditions: Congenital Cytomegalovirus Infection; Maternal Cytomegalovirus Infection
• Intervention / Treatment: Drug: CMV hyperimmune globulin; Other: Placebo

Detailed Description

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
• Enrollment (Actual): 399
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama - Birmingham
  • California
    • Stanford, California, United States, 94305-5317
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina - Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • Case Western Reserve-Metrohealth
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Womens Hospital of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas - Southwestern Medical Center
    • Galveston, Texas, United States, 77555
      • University of Texas - Galveston
    • Houston, Texas, United States, 77030
      • University of Texas - Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CMV hyperimmune globulin - Cytogam®; Infusion of Cytogam®, Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV)	Drug: CMV hyperimmune globulin; The study's active drug is Cytogam® which is an immunoglobulin G (IgG) containing a standardized amount of antibody to CMV. This drug contains pooled adult human plasma selected for high titers of antibody for CMV, and is administered intravenously at a dose of 100 mg/kg body weight.; Other Names: Cytogam; CMV-IGIV
Placebo Comparator: Placebo; IV 5% albumin diluted 1 to 9 with 5% Dextrose in water (D5W)	Other: Placebo; The matching placebo consists of AlbuRx® 5% diluted 1:9 with D5W. AlbuRx® 5% contains pooled adult human plasma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite 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.	3 weeks of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational hypertension	Gestational hypertension is a binary outcome defined by occurrence or non-occurrence of gestational hypertension. Gestational hypertension is a new onset hypertension during pregnancy	from approximately 20 weeks of gestation through delivery (maximum 42 weeks gestation)
Preeclampsia	Preeclampsia is a binary outcome defined by occurrence or non-occurrence of preeclampsia defined as a patient exhibiting new or worsening hypertension with proteinuria	approximately 20 weeks of gestation through 6 weeks postpartum
Placental abruption	Placental abruption is a binary outcome defined by occurrence or non-occurrence of placental abruption, defined as bleeding and contraction pain	From 16 weeks of gestation through delivery (maximum 42 weeks gestation)
Gestational age at delivery	Gestational age at delivery in weeks and days	Delivery
Gestational age at delivery before 37 weeks	Gestational age before 37 weeks gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 37 weeks gestation	Delivery before 37 weeks gestation
Gestational age at delivery 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	Delivery before 34 weeks gestation
Side effects	Occurrence or non-occurrence of a designated side effect of medication	From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation)
Treatment emergent severe adverse events	Treatment emergent serious adverse events is a composite binary outcome repeated over time (with the exception of maternal death) and is the occurrence of any one of the following: • Maternal death during the study and while pregnant from any cause related to pregnancy, but not from accidental or incidental causes • Anaphylaxis defined as an acute syndrome occurring within minutes to hours of administration of the study drug and consisting of one or more of the following sets of symptoms: - Angioedema (swelling) of the lips, tongue, uvula and/or throat - Generalized hives, flushing or pruritus accompanied by clinically significant hypotension (usually with tachycardia) - Objective signs of dyspnea such as stridor and/or wheezing • Pulmonary embolism confirmed by spiral CT (or strong suspicion on VQ scan if spiral CT not done) • Deep vein thrombosis confirmed by venogram	From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation)
Maternal viral load	Viral load following the last infusion where viral load is defined as the amount of cytomegalovirus in copies/mL	From approximately 14-27 weeks gestation through delivery (maximum 42 weeks gestation)
Fetal mortality	Fetal death	From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation)
Neonatal mortality	Death of a neonate that was born alive	0 days to 120 days of life
Primary outcome excluding terminations	Occurrence of the primary outcome including spontaneous fetal death but not termination	randomization to 3 weeks postpartum
Neonatal Head circumference	Neonatal head circumference measured within 72 hours of birth	72 hours postpartum
Birth weight	Birth weight as recorded in the medical record	Delivery
Growth restriction	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)	Delivery
Microcephaly	Microcephaly is a binary outcome defined by the occurrence or non-occurrence of head circumference <3rd percentile for gestational age, assessed specifically by sex of the infant based on Olsen's data from a U.S. population	Delivery
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	During pregnancy up to 3 weeks postpartum
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	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Ventriculomegaly	Ventriculomegaly is a binary outcome defined by the occurrence or non-occurrence of ventriculomegaly	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Retinopathy of prematurity (ROP)	Retinopathy of prematurity is a binary outcome defined by the occurrence or non-occurrence of retinopathy of prematurity, diagnosed by ophthalmologic examination of the retina and a diagnosis of Stage I (demarcation line in the retina) or greater.	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Respiratory distress syndrome	Respiratory distress syndrome is a binary outcome defined by the occurrence or non-occurrence of Respiratory distress syndrome (defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with an oxygen requirement and a chest x-ray that shows hypoventilation and reticulogranular infiltrates).	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Chronic lung disease	Neonatal chronic lung disease is a binary outcome defined by the occurrence or non-occurrence of chronic lung disease or bronchopulmonary dysplasia (BPD) defined as oxygen requirement at 28 days of life	28 days of life
Necrotizing enterocolitis (NEC)	Necrotizing enterocolitis (NEC) is a binary outcome defined by the occurrence or non-occurrence of NEC, defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Hyperbilirubinemia	Hyperbilirubinemia is a binary outcome defined by the occurrence or non-occurrence of hyperbilirubinemia. Peak total bilirubin of at least 15 mg% or the use of phototherapy	From birth to 1 week of life
Early neonatal sepsis	Early neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of sepsis occurring before 72 hours of birth	0 days of life to 72 hours of birth
Late neonatal sepsis	Late neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of sepsis occurring late than 72 hours of birth	Greater than 72 hours of birth to approximately 120 days of life or hospital discharge, whichever is sooner
Suspected neonatal sepsis	Suspected neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of suspected neonatal sepsis	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Neonatal pneumonia	Neonatal pneumonia is a binary outcome defined as the occurrence or non-occurrence of neonatal pneumonia	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Seizures / encephalopathy	Neonatal seizures/encephalopathy is a binary outcome defined as the occurrence or non-occurrence of seizures/encephalopathy	0 days to approximately 120 days of life or hospital discharge, whichever is sooner
Neonatal Length of hospital stay	Length of hospital stay, need for Neonatal Intensive Care Unit (NICU) or intermediate care admission and length of stay if admitted	birth to neonatal hospital discharge (usually a maximum of 120 days)
Infant or child death	Death of infant or child before the 24 month study exam	Birth to 24 month study exam
Sensorineural hearing loss	Sensorineural hearing loss is defined as the occurrence or non-occurrence of sensorineural hearing loss defined as unilateral and bilateral sensorineural hearing loss	12 and 24 months corrected age
Chorioretinitis	Chorioretinitis is defined as the occurrence or non-occurrence of chorioetinitis defined by ophthalmologic exam	2 years of age
Cognitive and Motor Scores from the Bayley Certified Scales of Infant Development III		12 and 24 months corrected age
Infant/Child composite outcome	Composite outcome at 24 months including any of the following attributable to congenital CMV infection: • Sensorineural hearing loss (unilateral and bilateral) • Developmental delay defined as Cognitive score < 70 or Motor score < 70 on the Bayley III • Chorioretinitis • Fetal loss or death of neonate, infant or child	24 month study exam
Child status at 24 months of age	Child status at age 24 months, classified as: • Fetal loss or death of neonate, infant or child • Congenital CMV infection with severe disability • Congenital CMV infection without severe disability • Infant not infected with CMV	24 month study exam
Failure to thrive	Failure to thrive defined as <10th percentile for weight at 12 and 24 months	12 months and 24 months of age
Child viral load	Viral load is defined as the amount of cytomegalovirus in copies/mL	12 and 24 months of age

Collaborators and Investigators

• Sponsor: The George Washington University Biostatistics Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Director: Andrew Bremer, M.D., MPH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Principal Investigator: Rebecca Clifton, PhD, George Washington University; Study Chair: Brenna Hughes, MD, Brown University

Publications and helpful links

General Publications

• Dinsmoor MJ, Fette LM, Hughes BL, Rouse DJ, Saade GR, Reddy UM, Allard D, Mallett G, Thom EA, Gyamfi-Bannerman C, Varner MW, Goodnight WH, Tita ATN, Costantine MM, Swamy GK, Heyborne KD, Chien EK, Chauhan SP, El-Sayed YY, Casey BM, Parry S, Simhan HN, Napolitano PG, Macones GA; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. Amniocentesis to diagnose congenital cytomegalovirus infection following maternal primary infection. Am J Obstet Gynecol MFM. 2022 Jul;4(4):100641. doi: 10.1016/j.ajogmf.2022.100641. Epub 2022 May 6.
• Hughes BL, Clifton RG, Rouse DJ, Saade GR, Dinsmoor MJ, Reddy UM, Pass R, Allard D, Mallett G, Fette LM, Gyamfi-Bannerman C, Varner MW, Goodnight WH, Tita ATN, Costantine MM, Swamy GK, Gibbs RS, Chien EK, Chauhan SP, El-Sayed YY, Casey BM, Parry S, Simhan HN, Napolitano PG, Macones GA; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection. N Engl J Med. 2021 Jul 29;385(5):436-444. doi: 10.1056/NEJMoa1913569.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: June 15, 2011
• First Submitted That Met QC Criteria: June 16, 2011
• First Posted (Estimate): June 20, 2011

Study Record Updates

• Last Update Posted (Actual): September 22, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Perinatology; Cytomegalovirus immune globulin; Cytogam; CMVIG infusions
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections
• Other Study ID Numbers: HD36801-CMV; U10HD036801 (U.S. NIH Grant/Contract); UG1HD087230 (U.S. NIH Grant/Contract); UG1HD087192 (U.S. NIH Grant/Contract); U10HD027869 (U.S. NIH Grant/Contract); U10HD034116 (U.S. NIH Grant/Contract); U10HD034208 (U.S. NIH Grant/Contract); U10HD040500 (U.S. NIH Grant/Contract); U10HD040485 (U.S. NIH Grant/Contract); U10HD040544 (U.S. NIH Grant/Contract); U10HD040545 (U.S. NIH Grant/Contract); U10HD040560 (U.S. NIH Grant/Contract); U10HD040512 (U.S. NIH Grant/Contract); U10HD053097 (U.S. NIH Grant/Contract); U10HD027915 (U.S. NIH Grant/Contract); U10HD068282 (U.S. NIH Grant/Contract); U10HD068258 (U.S. NIH Grant/Contract); U10HD068268 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The dataset will be shared per NIH policy after the completion and publication of the main analyses. Requests for datasets can be sent to mfmudatasets@bsc.gwu.edu.