Intrauterine Growth Restriction, IUGR, Villitis
Conditions
Brief summary
Intrauterine growth restriction (IUGR) is caused when the placenta cannot provide enough nutrients to allow normal growth of the fetus during pregnancy. It is unclear why IUGR happens, but an increase in inflammatory T cells in the placenta known as villitis of unknown etiology (VUE) is observed in many IUGR infants. The investigators aim to develop ultrasound methods for diagnosing VUE to understand it's role in IUGR.
Detailed description
Intrauterine growth restriction (IUGR) occurs in 3-10% of all pregnancies and is associated with significant morbidity and mortality during pregnancy, after birth and throughout the child's lifespan. IUGR is caused by the inability of the placental vasculature to provide enough oxygen and nutrients to support the fetus; yet, the mechanisms leading to disruption of placental vasculature are unknown. The placenta of \ 50% of IUGR fetuses are infiltrated with inflammatory cells, specifically maternal T cells, which destroy placental blood vessels that support the fetus. This infiltration of T cells is known as villitis of unknown etiology (VUE). The diagnosis of VUE is problematic because it occurs without clinical signs and symptoms of maternal (or fetal) distress and puts the fetus at significant risk of demise. Additionally, VUE commonly recurs in subsequent pregnancies putting future offspring at risk. Yet, the exact prevalence of VUE and its significance in IUGR pathogenesis and outcomes are poorly understood as VUE is only diagnosed after the infant is outside the womb. Therefore, the study aims to recognize risk factors and cellular mechanisms associated with VUE and develop methods for diagnosing and treating VUE in utero, in order to improve infant health.
Interventions
DIAGNOSTIC_TESTComprehensive Doppler Ultrasound of the Placenta
Ultrasound measures to be collected include uterine artery (UtA) and umbilical artery (UA), systolic/diastolic (S/D) ratio, resistance index (RI), pulsatility index (PI) and presence of early diastolic notch.
OTHERVerasonics Ultrasound scanner (ultra-sensitive Doppler imaging)
In addition, a Verasonics ultrasound scanner will be used for ultra-sensitive Doppler imaging. Data will be collected on vessel density, periphery-to-center vessel density ratio (VDR) and microvessel morphology.
Sponsors
Mayo Clinic
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
for IUGR study cohort: * Pregnancy \> 28 weeks gestation * Diagnosis of Intrauterine Growth Restriction (IUGR) before admission for labor and delivery * Weight \> 110 lbs (50 kg) * Ability to understand and provide written informed consent Inclusion Criteria for control cohort: * Pregnancy \> 28 weeks gestation * No known pregnancy complications at prenatal obstetrical visit (+/- 1 week gestational age of matched subject in IUGR cohort) * Weight \> 110 lbs (50 kg) * Ability to understand and provide written informed consent
Exclusion criteria
* Known immunodeficiency or pregnancy complication (i.e. preeclampsia or gestational diabetes) * Known autoimmune disease (e.g., rheumatoid arthritis or systemic lupus erythematosus) or chronic hypertension * Chronic, active viral infections, including HIV-1/2, HTLV-1/2, Hepatitis B or C * Solid organ or transplant recipient * Current smokers (tobacco exposure within 30 days of registration) * Conceptions from assisted reproductive technology (prior Clomid use is allowed) * Multiple gestation * Ruptured membranes * Pregnancy \<28 weeks gestation * Not planning on delivering at Mayo Clinic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Placental Pathology Indicating Chronic Villitis | Gestational age up to 42 weeks | Using the Amsterdam criteria, following delivery, placentae will be histologically examined for placental villitis (presence of maternal T cells) and graded by severity. High grade involves greater than 10 villi while low grade affects fewer than 10 villi. |
| Systolic(S)/Diastolic(D) Ratio | Gestational Age of 34-36 weeks | S = Systolic peak (max velocity); Maximum velocity during contraction of the fetal heart. D = End-diastolic flow; Continuing forward flow in the umbilical artery during the relaxation phase of the heartbeat. S/D ratio = (systolic / diastolic ratio) |
| Resistance Index (RI) | Gestational Age of 34-36 weeks | Resistance index (RI) = (systolic velocity - diastolic velocity / systolic velocity) |
| Pulsatility Index (PI) | Gestational age of 34-36 weeks | Pulsatility index (PI) = (systolic velocity - diastolic velocity / mean velocity) |
| Number of Participants With Uterine Artery Indices Completed | Gestational age of 34-36 weeks | Measured by Doppler and 3D microvessel imaging, used to calculate outcomes 3-5 |
| Number of Patients With Umbilical Artery Indices Completed | Gestational Age of 34-36 weeks | Measured by Doppler and 3D microvessel imaging, used to calculate outcomes 3-5 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preterm Labor | Gestational age up to 37 weeks | Pregnancy that delivered prior to 37 weeks gestational age |
| Birth Weight of Infant | Gestational age up to 42 weeks | Weight of infant at time of birth |
| Gestational Age at Birth | Gestational age up to 42 weeks | The gestational age in weeks of when the baby was delivered. |
Countries
United States
Participant flow
Recruitment details
Enrollment from September 2020 through March 2023
Participants by arm
| Arm | Count |
|---|---|
| Intrauterine Growth Restriction Pregnant women carrying a fetus identified with intrauterine growth restriction during the third trimester (\>28 weeks gestation)
Comprehensive Doppler Ultrasound of the Placenta: Ultrasound measures to be collected include uterine artery (UtA) and umbilical artery (UA), systolic/diastolic (S/D) ratio, resistance index (RI), pulsatility index (PI) and presence of early diastolic notch.
Verasonics Ultrasound scanner (ultra-sensitive Doppler imaging): In addition, a Verasonics ultrasound scanner will be used for ultra-sensitive Doppler imaging. Data will be collected on vessel density, periphery-to-center vessel density ratio (VDR) and microvessel morphology. | 40 |
| Normal Pregnancy Pregnant women identified with an uncomplicated pregnancy during the third trimester (\>28 weeks), matched for fetal sex and gestational age with women enrolled in the IUGR group.
Comprehensive Doppler Ultrasound of the Placenta: Ultrasound measures to be collected include uterine artery (UtA) and umbilical artery (UA), systolic/diastolic (S/D) ratio, resistance index (RI), pulsatility index (PI) and presence of early diastolic notch.
Verasonics Ultrasound scanner (ultra-sensitive Doppler imaging): In addition, a Verasonics ultrasound scanner will be used for ultra-sensitive Doppler imaging. Data will be collected on vessel density, periphery-to-center vessel density ratio (VDR) and microvessel morphology. | 20 |
| Total | 60 |
Baseline characteristics
| Characteristic | Intrauterine Growth Restriction | Normal Pregnancy | Total |
|---|---|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 5.2 | 30.8 years STANDARD_DEVIATION 3.9 | 31.4 years STANDARD_DEVIATION 4.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 17 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Gestational Diabetes | 8 Participants | 1 Participants | 9 Participants |
| Gravidity | 2.7 Pregnancies STANDARD_DEVIATION 1.58 | 1.9 Pregnancies STANDARD_DEVIATION 1.33 | 2.4 Pregnancies STANDARD_DEVIATION 1.53 |
| Hypertension | 9 Participants | 4 Participants | 13 Participants |
| Hypothyroidism | 5 Participants | 2 Participants | 7 Participants |
| Maternal BMI at ultrasound | 28.7 kg/m^2 STANDARD_DEVIATION 5.62 | 28.3 kg/m^2 STANDARD_DEVIATION 4.2 | 28.5 kg/m^2 STANDARD_DEVIATION 5.16 |
| Preeclampsia | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 33 Participants | 18 Participants | 51 Participants |
| Region of Enrollment United States | 40 participants | 20 participants | 60 participants |
| Sex: Female, Male Female | 40 Participants | 20 Participants | 60 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 20 |
| other Total, other adverse events | 0 / 40 | 0 / 20 |
| serious Total, serious adverse events | 0 / 40 | 0 / 20 |
Outcome results
Primary
Number of Participants With Placental Pathology Indicating Chronic Villitis
Using the Amsterdam criteria, following delivery, placentae will be histologically examined for placental villitis (presence of maternal T cells) and graded by severity. High grade involves greater than 10 villi while low grade affects fewer than 10 villi.
Time frame: Gestational age up to 42 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intrauterine Growth Restriction | Number of Participants With Placental Pathology Indicating Chronic Villitis | 8 Participants |
| Normal Pregnancy | Number of Participants With Placental Pathology Indicating Chronic Villitis | 7 Participants |
Primary
Number of Participants With Uterine Artery Indices Completed
Measured by Doppler and 3D microvessel imaging, used to calculate outcomes 3-5
Time frame: Gestational age of 34-36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intrauterine Growth Restriction | Number of Participants With Uterine Artery Indices Completed | 13 Participants |
| Normal Pregnancy | Number of Participants With Uterine Artery Indices Completed | 3 Participants |
Primary
Number of Patients With Umbilical Artery Indices Completed
Measured by Doppler and 3D microvessel imaging, used to calculate outcomes 3-5
Time frame: Gestational Age of 34-36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intrauterine Growth Restriction | Number of Patients With Umbilical Artery Indices Completed | 29 Participants |
| Normal Pregnancy | Number of Patients With Umbilical Artery Indices Completed | 8 Participants |
Primary
Pulsatility Index (PI)
Pulsatility index (PI) = (systolic velocity - diastolic velocity / mean velocity)
Time frame: Gestational age of 34-36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intrauterine Growth Restriction | Pulsatility Index (PI) | 1.0 Ratio | Standard Deviation 0.2 |
| Normal Pregnancy | Pulsatility Index (PI) | 0.7 Ratio | Standard Deviation 0 |
Primary
Resistance Index (RI)
Resistance index (RI) = (systolic velocity - diastolic velocity / systolic velocity)
Time frame: Gestational Age of 34-36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intrauterine Growth Restriction | Resistance Index (RI) | 0.6 Ratio | Standard Deviation 0.7 |
| Normal Pregnancy | Resistance Index (RI) | 0.6 Ratio | Standard Deviation 0.08 |
Primary
Systolic(S)/Diastolic(D) Ratio
S = Systolic peak (max velocity); Maximum velocity during contraction of the fetal heart. D = End-diastolic flow; Continuing forward flow in the umbilical artery during the relaxation phase of the heartbeat. S/D ratio = (systolic / diastolic ratio)
Time frame: Gestational Age of 34-36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intrauterine Growth Restriction | Systolic(S)/Diastolic(D) Ratio | 2.8 ratio | Standard Deviation 0.7 |
| Normal Pregnancy | Systolic(S)/Diastolic(D) Ratio | 2.3 ratio | Standard Deviation 0.4 |
Secondary
Birth Weight of Infant
Weight of infant at time of birth
Time frame: Gestational age up to 42 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intrauterine Growth Restriction | Birth Weight of Infant | 2598 Grams | Standard Deviation 457 |
| Normal Pregnancy | Birth Weight of Infant | 3348.5 Grams | Standard Deviation 444 |
Secondary
Gestational Age at Birth
The gestational age in weeks of when the baby was delivered.
Time frame: Gestational age up to 42 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intrauterine Growth Restriction | Gestational Age at Birth | 39.2 Weeks | Standard Deviation 1.3 |
| Normal Pregnancy | Gestational Age at Birth | 38.1 Weeks | Standard Deviation 1.5 |
Secondary
Preterm Labor
Pregnancy that delivered prior to 37 weeks gestational age
Time frame: Gestational age up to 37 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intrauterine Growth Restriction | Preterm Labor | 2 Participants |
| Normal Pregnancy | Preterm Labor | 0 Participants |