Predicting Placental Pathologies by Ultrasound Imaging

Study Overview
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Brief Summary
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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
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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.

Official Title
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Predicting Placental Pathologies by Ultrasound Imaging of the Human Placenta During Gestation

Conditions
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Intrauterine Growth Restriction, Villitis, IUGR

Intervention / Treatment
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* Diagnostic Test: Comprehensive Doppler Ultrasound of the Placenta
* Other: Verasonics Ultrasound scanner (ultra-sensitive Doppler imaging)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Intrauterine Growth Restriction<br>Pregnant women carrying a fetus identified with intrauterine growth restriction during the third trimester (>28 weeks gestation) | Diagnostic Test: Comprehensive Doppler Ultrasound of the Placenta<br>* 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.<br>Other: Verasonics Ultrasound scanner (ultra-sensitive Doppler imaging)<br>* 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.<br>|
| Normal pregnancy<br>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. | Diagnostic Test: Comprehensive Doppler Ultrasound of the Placenta<br>* 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.<br>Other: Verasonics Ultrasound scanner (ultra-sensitive Doppler imaging)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine artery indices | Measured by Doppler and 3D microvessel imaging, used to calculate outcomes 3-5 | 34-36 weeks | 
| Umbilical artery indices | Measured by Doppler and 3D microvessel imaging, used to calculate outcomes 3-5 | 34-36 weeks | 
| 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) | 34-36 weeks | 
| Resistance index (RI) | Resistance index (RI) = (systolic velocity - diastolic velocity / systolic velocity) | 34-36 weeks | 
| Pulsatility index (PI) | Pulsatility index (PI) = (systolic velocity - diastolic velocity / mean velocity) | 34-36 weeks | 
| Placental pathology | 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. | up to 42 weeks |