Congenital Cytomegalovirus Infection, Maternal Cytomegalovirus Infection
Conditions
Keywords
Perinatology, Cytomegalovirus immune globulin, Cytogam, CMVIG infusions
Brief summary
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.
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.
Interventions
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.
OTHERPlacebo
The matching placebo consists of AlbuRx® 5% diluted 1:9 with D5W. AlbuRx® 5% contains pooled adult human plasma.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The George Washington University Biostatistics Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Composite Primary Outcome | From randomization through 3 weeks of life | 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. |
| Number of Participants Who Had a Fetus or Neonate With CMV Infection | From randomization through 3 weeks of life | Component of composite primary outcome |
| Number of Participants Who Had a Neonatal Death Without CMV Infection | From randomization through 3 weeks of life | component of composite primary outcome |
| Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection | From randomization through 3 weeks of life | component of primary composite outcome |
| Number of Participants With Fetal Death Without Proven CMV Infection | From randomization through delivery | component of primary composite outcome |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Yes or no to Medication Side Effects | From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) | Occurrence or non-occurrence of a designated side effect of medication |
| Number of Participants Who Had a Fetal or Neonatal Death | From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) up to 120 days of life | Fetal death or death of a neonate born alive |
| Median Neonatal Head Circumference | 72 hours postpartum | Neonatal head circumference measured within 72 hours of birth |
| Median Birth Weight | Delivery | Birth weight as recorded in the medical record |
| Number of Participants With Fetal Growth Restriction | Delivery | 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) |
| Number of Participants With Symptomatic CMV Infection | During pregnancy up to 3 weeks postpartum | 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 |
| Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 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 |
| Number of Neonates With Ventriculomegaly | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | Ventriculomegaly is a binary outcome defined by the occurrence or non-occurrence of ventriculomegaly |
| Number of Neonates With Retinopathy of Prematurity (ROP) | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 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. |
| Number of Neonates With Respiratory Distress Syndrome | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 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). |
| Number of Neonates With Chronic Lung Disease | 28 days of life | 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 |
| Number of Neonates With Necrotizing Enterocolitis (NEC) | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 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. |
| Number of Participants With Gestational Hypertension or Preeclampsia | from randomization through discharge from the hospital | 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 |
| Number of Neonates With Suspected Neonatal Sepsis | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | Suspected neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of suspected neonatal sepsis |
| Number of Neonates With Neonatal Pneumonia | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | Neonatal pneumonia is a binary outcome defined as the occurrence or non-occurrence of neonatal pneumonia |
| Number of Neonates Experiencing Seizures / Encephalopathy | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | Neonatal seizures/encephalopathy is a binary outcome defined as the occurrence or non-occurrence of seizures/encephalopathy |
| Median Length of Neonatal Hospital Stay | birth to neonatal hospital discharge (usually a maximum of 120 days) | Length of hospital stay, need for Neonatal Intensive Care Unit (NICU) or intermediate care admission and length of stay if admitted |
| Number of Participants Experiencing Infant or Child Death | Birth to 24 month study exam | Death of infant or child before the 24 month study exam |
| Number of Children With Sensorineural Hearing Loss | 12 and 24 months corrected age | Sensorineural hearing loss is defined as the occurrence or non-occurrence of sensorineural hearing loss defined as unilateral and bilateral sensorineural hearing loss |
| Number of Children Diagnosed With Chorioretinitis | 2 years of age | Chorioretinitis is defined as the occurrence or non-occurrence of chorioretinitis defined by ophthalmologic exam |
| Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 12 and 24 months corrected age | The Bayley Scales of Infant and Toddler Development® \| Third Edition (Bayley®-III), is a comprehensive tool to identify development issues during early childhood. The Bayley-III Cognitive Scale subtests assess cognitive function through the use of memory, problem solving and manipulation subtests. Scores on individual Cognitive subtests range from 1 (worst outcome) to 19 (better outcome) (Mean 10, SD 3). Individual subtest scores between 8 and 12 are considered average. The raw scores on the subtests are converted to scaled scores based on American norms by age. Cognitive Scale composite scores range from 55 (low, worse outcome) to 155 (high, better outcome) (mean 100; SD 15). Severe disability was defined as a composite score \<70. |
| Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 12 and 24 months corrected age | The Bayley Scales of Infant and Toddler Development® \| Third Edition (Bayley®-III), is a comprehensive tool to identify development issues during early childhood. The Bayley-III Motor Scale subtests assess motor function through fine motor and gross motor subtests. Scores on individual Motor subtests range from 1 (worst outcome) to 19 (better outcome) (Mean 10, SD 3). Individual subtest scores between 8 and 12 are considered average. The raw scores on the subtests are converted to scaled scores based on American norms by age. Motor Scale composite scores range from 55 (low, worse outcome) to 155 (high, better outcome) (mean 100; SD 15). Severe disability was defined as a composite score \<70. |
| Number of Infants or Children With the Composite Outcome | 24 month study exam | 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 |
| Overall Child Status at 24 Months of Age | 24 month study exam | 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 |
| Failure to Thrive at 24 Months | 24 months of age | Failure to thrive defined as \<10th percentile for weight at 24 months |
| Number of Neonates With Hyperbilirubinemia | From birth to 1 week of life | 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 |
| Number of Participants With Placental Abruption | From randomization through delivery (maximum 42 weeks gestation) | Placental abruption is a binary outcome defined by occurrence or non-occurrence of placental abruption, defined as bleeding and contraction pain |
| Median Gestational Age at Delivery | Delivery | Gestational age at delivery in weeks |
| Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks | Delivery before 37 weeks gestation | Gestational age before 37 weeks gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 37 weeks gestation |
| Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days | Delivery before 34 weeks gestation | Gestational age before 34 weeks, 0 days gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 34 weeks gestation |
Countries
United States
Participant flow
Recruitment details
206,082 Pregnant women were assessed for eligibility (screened for primary CMV infection). 205,683 Were excluded.
Participants by arm
| Arm | Count |
|---|---|
| CMV Hyperimmune Globulin - Cytogam® Infusion of Cytogam®, Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV)
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. | 206 |
| Placebo IV 5% albumin diluted 1 to 9 with 5% Dextrose in water (D5W)
Placebo: The matching placebo consists of AlbuRx® 5% diluted 1:9 with D5W. AlbuRx® 5% contains pooled adult human plasma. | 193 |
| Total | 399 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 2 |
Baseline characteristics
| Characteristic | CMV Hyperimmune Globulin - Cytogam® | Placebo | Total |
|---|---|---|---|
| 1 or more children in day care | 83 Participants | 78 Participants | 161 Participants |
| 1 or more children living at home | 150 Participants | 140 Participants | 290 Participants |
| Age, Continuous | 27.2 years STANDARD_DEVIATION 6.3 | 28.5 years STANDARD_DEVIATION 6 | 27.8 years STANDARD_DEVIATION 6.2 |
| Alcohol use | 21 Participants | 24 Participants | 45 Participants |
| Avidity index at randomization | 29.7 avidity index STANDARD_DEVIATION 14.6 | 29.9 avidity index STANDARD_DEVIATION 13.6 | 29.8 avidity index STANDARD_DEVIATION 14.1 |
| Body-mass index at randomization | 27.2 kg/m^2 STANDARD_DEVIATION 7 | 26.9 kg/m^2 STANDARD_DEVIATION 7 | 27.1 kg/m^2 STANDARD_DEVIATION 7 |
| CMV infection at screening IgM+, IgG+, low avidity (low avidity defined as less than 50 percent) | 200 Participants | 183 Participants | 383 Participants |
| CMV infection at screening IgM+, IgG seroconversion | 5 Participants | 10 Participants | 15 Participants |
| CMV infection at screening No primary CMV infection - randomization error | 1 Participants | 0 Participants | 1 Participants |
| Days from screening to randomization | 25.5 days STANDARD_DEVIATION 9.1 | 25.2 days STANDARD_DEVIATION 8.2 | 25.3 days STANDARD_DEVIATION 8.7 |
| Distribution of weeks gestation at randomization ≤11 weeks, 6 days | 26 Participants | 36 Participants | 62 Participants |
| Distribution of weeks gestation at randomization 12 weeks, 0 days to 19 weeks, 6 days | 142 Participants | 126 Participants | 268 Participants |
| Distribution of weeks gestation at randomization ≥20 weeks, 0 days | 38 Participants | 31 Participants | 69 Participants |
| Education | 14.1 years STANDARD_DEVIATION 2.1 | 14.2 years STANDARD_DEVIATION 2.3 | 14.2 years STANDARD_DEVIATION 2.2 |
| Married or living with partner | 145 Participants | 142 Participants | 287 Participants |
| Mean weeks gestation at randomization | 16.2 weeks STANDARD_DEVIATION 3.9 | 15.6 weeks STANDARD_DEVIATION 4.1 | 15.9 weeks STANDARD_DEVIATION 4 |
| Nulliparous | 75 Participants | 62 Participants | 137 Participants |
| Occupational exposure | 78 Participants | 63 Participants | 141 Participants |
| Race/Ethnicity, Customized Hispanic | 30 Participants | 33 Participants | 63 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 35 Participants | 30 Participants | 65 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 135 Participants | 124 Participants | 259 Participants |
| Race/Ethnicity, Customized Other, unknown, or more than one race or ethnic group | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 206 Participants | 193 Participants | 399 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tobacco use | 22 Participants | 23 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 206 | 0 / 193 |
| other Total, other adverse events | 8 / 206 | 7 / 193 |
| serious Total, serious adverse events | 32 / 206 | 25 / 193 |
Outcome results
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Who Had a Fetus or Neonate With CMV Infection | 36 Participants |
| Placebo | Number of Participants Who Had a Fetus or Neonate With CMV Infection | 32 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Who Had a Neonatal Death Without CMV Infection | 0 Participants |
| Placebo | Number of Participants Who Had a Neonatal Death Without CMV Infection | 0 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection | 7 Participants |
| Placebo | Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection | 3 Participants |
Primary
Number of Participants With Fetal Death Without Proven CMV Infection
component of primary composite outcome
Time frame: From randomization through delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With Fetal Death Without Proven CMV Infection | 3 Participants |
| Placebo | Number of Participants With Fetal Death Without Proven CMV Infection | 2 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With the Composite Primary Outcome | 46 Participants |
| Placebo | Number of Participants With the Composite Primary Outcome | 37 Participants |
p-value: 0.4295% CI: [0.8, 1.72]Chi-squared
Secondary
Failure to Thrive at 24 Months
Failure to thrive defined as \<10th percentile for weight at 24 months
Time frame: 24 months of age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Failure to Thrive at 24 Months | 20 Participants |
| Placebo | Failure to Thrive at 24 Months | 21 Participants |
p-value: 0.84Chi-squared
Secondary
Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)
The Bayley Scales of Infant and Toddler Development® \| Third Edition (Bayley®-III), is a comprehensive tool to identify development issues during early childhood. The Bayley-III Cognitive Scale subtests assess cognitive function through the use of memory, problem solving and manipulation subtests. Scores on individual Cognitive subtests range from 1 (worst outcome) to 19 (better outcome) (Mean 10, SD 3). Individual subtest scores between 8 and 12 are considered average. The raw scores on the subtests are converted to scaled scores based on American norms by age. Cognitive Scale composite scores range from 55 (low, worse outcome) to 155 (high, better outcome) (mean 100; SD 15). Severe disability was defined as a composite score \<70.
Time frame: 12 and 24 months corrected age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 96.2 score on a scale | Standard Deviation 15.1 |
| Placebo | Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 97.1 score on a scale | Standard Deviation 13.5 |
Secondary
Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)
The Bayley Scales of Infant and Toddler Development® \| Third Edition (Bayley®-III), is a comprehensive tool to identify development issues during early childhood. The Bayley-III Motor Scale subtests assess motor function through fine motor and gross motor subtests. Scores on individual Motor subtests range from 1 (worst outcome) to 19 (better outcome) (Mean 10, SD 3). Individual subtest scores between 8 and 12 are considered average. The raw scores on the subtests are converted to scaled scores based on American norms by age. Motor Scale composite scores range from 55 (low, worse outcome) to 155 (high, better outcome) (mean 100; SD 15). Severe disability was defined as a composite score \<70.
Time frame: 12 and 24 months corrected age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 98.7 score on a scale | Standard Deviation 16.4 |
| Placebo | Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 101.9 score on a scale | Standard Deviation 14.9 |
Secondary
Median Birth Weight
Birth weight as recorded in the medical record
Time frame: Delivery
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Median Birth Weight | 3268 grams | Standard Deviation 657 |
| Placebo | Median Birth Weight | 3303 grams | Standard Deviation 548 |
95% CI: [-157, 87]
Secondary
Median Gestational Age at Delivery
Gestational age at delivery in weeks
Time frame: Delivery
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Median Gestational Age at Delivery | 38.2 weeks | Standard Deviation 4.1 |
| Placebo | Median Gestational Age at Delivery | 38.6 weeks | Standard Deviation 3.6 |
Secondary
Median Length of Neonatal Hospital Stay
Length of hospital stay, need for Neonatal Intensive Care Unit (NICU) or intermediate care admission and length of stay if admitted
Time frame: birth to neonatal hospital discharge (usually a maximum of 120 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Median Length of Neonatal Hospital Stay | 2 days |
| Placebo | Median Length of Neonatal Hospital Stay | 2 days |
Secondary
Median Neonatal Head Circumference
Neonatal head circumference measured within 72 hours of birth
Time frame: 72 hours postpartum
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Median Neonatal Head Circumference | 33.9 centimeters | Standard Deviation 2.1 |
| Placebo | Median Neonatal Head Circumference | 34.1 centimeters | Standard Deviation 1.9 |
95% CI: [-0.66, 0.15]
Secondary
Number of Children Diagnosed With Chorioretinitis
Chorioretinitis is defined as the occurrence or non-occurrence of chorioretinitis defined by ophthalmologic exam
Time frame: 2 years of age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Children Diagnosed With Chorioretinitis | 0 Participants |
| Placebo | Number of Children Diagnosed With Chorioretinitis | 1 Participants |
Secondary
Number of Children With 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
Time frame: 12 and 24 months corrected age
Population: Hearing data was not available for approximately 25% of children due to loss to followup or consent refusal.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Children With Sensorineural Hearing Loss | 2 Participants |
| Placebo | Number of Children With Sensorineural Hearing Loss | 7 Participants |
Secondary
Number of Infants or Children With the 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
Time frame: 24 month study exam
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Infants or Children With the Composite Outcome | 20 Participants |
| Placebo | Number of Infants or Children With the Composite Outcome | 15 Participants |
p-value: 0.3795% CI: [0.7, 2.5]Chi-squared
Secondary
Number of Neonates Experiencing Seizures / Encephalopathy
Neonatal seizures/encephalopathy is a binary outcome defined as the occurrence or non-occurrence of seizures/encephalopathy
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates Experiencing Seizures / Encephalopathy | 0 Participants |
| Placebo | Number of Neonates Experiencing Seizures / Encephalopathy | 0 Participants |
Secondary
Number of Neonates With 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
Time frame: 28 days of life
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Chronic Lung Disease | 0 Participants |
| Placebo | Number of Neonates With Chronic Lung Disease | 0 Participants |
Secondary
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
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage | 1 Participants |
| Placebo | Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage | 0 Participants |
Secondary
Number of Neonates With 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
Time frame: From birth to 1 week of life
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Hyperbilirubinemia | 13 Participants |
| Placebo | Number of Neonates With Hyperbilirubinemia | 19 Participants |
95% CI: [0.32, 1.23]
Secondary
Number of Neonates With 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.
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Necrotizing Enterocolitis (NEC) | 0 Participants |
| Placebo | Number of Neonates With Necrotizing Enterocolitis (NEC) | 0 Participants |
Secondary
Number of Neonates With Neonatal Pneumonia
Neonatal pneumonia is a binary outcome defined as the occurrence or non-occurrence of neonatal pneumonia
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Neonatal Pneumonia | 1 Participants |
| Placebo | Number of Neonates With Neonatal Pneumonia | 2 Participants |
95% CI: [0.17, 5.23]
Secondary
Number of Neonates With 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).
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Respiratory Distress Syndrome | 5 Participants |
| Placebo | Number of Neonates With Respiratory Distress Syndrome | 10 Participants |
95% CI: [0.17, 1.38]
Secondary
Number of Neonates With 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.
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Retinopathy of Prematurity (ROP) | 1 Participants |
| Placebo | Number of Neonates With Retinopathy of Prematurity (ROP) | 1 Participants |
95% CI: [0.03, 31.5]
Secondary
Number of Neonates With Suspected Neonatal Sepsis
Suspected neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of suspected neonatal sepsis
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Suspected Neonatal Sepsis | 14 Participants |
| Placebo | Number of Neonates With Suspected Neonatal Sepsis | 16 Participants |
95% CI: [0.42, 1.68]
Secondary
Number of Neonates With Ventriculomegaly
Ventriculomegaly is a binary outcome defined by the occurrence or non-occurrence of ventriculomegaly
Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Neonates With Ventriculomegaly | 1 Participants |
| Placebo | Number of Neonates With Ventriculomegaly | 0 Participants |
Secondary
Number of Participants Experiencing Infant or Child Death
Death of infant or child before the 24 month study exam
Time frame: Birth to 24 month study exam
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Experiencing Infant or Child Death | 10 Participants |
| Placebo | Number of Participants Experiencing Infant or Child Death | 5 Participants |
Secondary
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)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Reporting Yes or no to Medication Side Effects | Participants reported no side effects | 125 Participants |
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Reporting Yes or no to Medication Side Effects | Participants reported any side effects | 81 Participants |
| Placebo | Number of Participants Reporting Yes or no to Medication Side Effects | Participants reported no side effects | 131 Participants |
| Placebo | Number of Participants Reporting Yes or no to Medication Side Effects | Participants reported any side effects | 62 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Who Had a Fetal or Neonatal Death | 10 Participants |
| Placebo | Number of Participants Who Had a Fetal or Neonatal Death | 5 Participants |
95% CI: [0.66, 5.41]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days | 12 Participants |
| Placebo | Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days | 7 Participants |
95% CI: [0.65, 4.01]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks | 25 Participants |
| Placebo | Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks | 16 Participants |
95% CI: [0.81, 2.67]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With Fetal Growth Restriction | 20 Participants |
| Placebo | Number of Participants With Fetal Growth Restriction | 10 Participants |
95% CI: [0.92, 3.99]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With Gestational Hypertension or Preeclampsia | 24 Participants |
| Placebo | Number of Participants With Gestational Hypertension or Preeclampsia | 14 Participants |
95% CI: [0.86, 3.03]
Secondary
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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With Placental Abruption | 3 Participants |
| Placebo | Number of Participants With Placental Abruption | 1 Participants |
95% CI: [0.29, 72.42]
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Number of Participants With Symptomatic CMV Infection | 23 Participants |
| Placebo | Number of Participants With Symptomatic CMV Infection | 15 Participants |
Secondary
Overall 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
Time frame: 24 month study exam
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CMV Hyperimmune Globulin - Cytogam® | Overall Child Status at 24 Months of Age | Congenital CMV with severe disability | 6 Participants |
| CMV Hyperimmune Globulin - Cytogam® | Overall Child Status at 24 Months of Age | Not infected with CMV with severe disability | 4 Participants |
| CMV Hyperimmune Globulin - Cytogam® | Overall Child Status at 24 Months of Age | Congenital CMV without severe disability | 21 Participants |
| CMV Hyperimmune Globulin - Cytogam® | Overall Child Status at 24 Months of Age | Not infected with CMV and no disabilities | 107 Participants |
| CMV Hyperimmune Globulin - Cytogam® | Overall Child Status at 24 Months of Age | Death or fetal loss | 10 Participants |
| Placebo | Overall Child Status at 24 Months of Age | Not infected with CMV and no disabilities | 115 Participants |
| Placebo | Overall Child Status at 24 Months of Age | Death or fetal loss | 5 Participants |
| Placebo | Overall Child Status at 24 Months of Age | Congenital CMV with severe disability | 7 Participants |
| Placebo | Overall Child Status at 24 Months of Age | Congenital CMV without severe disability | 19 Participants |
| Placebo | Overall Child Status at 24 Months of Age | Not infected with CMV with severe disability | 3 Participants |
p-value: 0.26Chi-squared