Significance: Fetal growth restriction (FGR) is an independent predictor of infant and lifelong morbidity and mortality of non-anomalous fetuses. However, fetal biometry alone does not reliably distinguish between small fetuses at risk for poor outcomes from those that are constitutionally small. Considerable efforts have been directed toward developing more robust methods for the detection and monitoring of small fetuses at risk for adverse outcomes. Conventional efforts for measuring umbilical venous blood flow (UVBF), using conventional 2D vessel diameter measurements with Doppler velocimetry, have been challenging due to technical factors that make it impractical for routine clinical practice. We will address this problem by using 3D sonography to measure umbilical venous blood flow (3D UVBF). This approach combines color flow Doppler ultrasound with a 2D array transducer to quantify volume flow in a manner that does not require a priori knowledge of small vessel diameter, Doppler insonation angle, flow velocity profile, or vessel geometry. Hypotheses: 1) 3D UVBF is an accurate and reproducible sonographic parameter for measuring umbilical venous flow throughout gestation; 2) Reference standards for 3D UVBF will be readily generated that provide a necessary framework for prospective analyses; and 3) A predictable and progressive circulatory deterioration pattern, based on 3D UVBF, occurs significantly more frequently among small fetuses (EFW < 10th%) with adverse outcomes when compared to other small fetuses without complications. Preliminary Data: We have shown that the 3D UVBF % error, relative to average measured arterial and venous flow, was ? 10% for 8 of 9 measurements in exteriorized fetuses of pregnant ewes. Lower than expected 3D UVBF values were found in 2 of 7 fetuses from human pregnancies that later developed FGR or preeclampsia (Pinter S, et al. J Ultrasound Med 37:1633-1640, 2018). In further reproducibility studies, the 3D UVBF intra-subject and intra-measurement relative standard errors (RSE) were 12.1 5.9 and 5.6 1.9 % (mean SD), respectively (n=35).
Specific Aims : We propose to validate 3D UVBF, develop 3D UVBF reference standards, and provide detailed observations of circulatory changes in small fetuses with EFW < 10th%.
In Specific Aim 1, in-vitro flow phantom experiments and reproducibility studies in pregnant women will examine the accuracy and reproducibility of 3D UVBF.
In Specific Aim 2, serial ultrasound scans will develop prescriptive 3D UVBF reference standards in 400 non-anomalous fetuses with normal growth outcomes.
In Specific Aim 3, circulatory patterns of multi-vessel Doppler velocimetry and 3D UVBF changes will be determined in a prospective cohort of 1100 small fetuses. The added value of 3D UVBF and related Doppler circulatory patterns in identifying small fetuses with adverse perinatal outcomes or neonatal morbidities will be examined. Successful execution of our Aims should establish 3D UVBF as a reproducible circulatory parameter that is accurate and clinically applicable as early as the first trimester. Our approach may improve detection and monitoring of small fetuses before conventional imaging predictors of adverse pregnancy outcomes become apparent.

Public Health Relevance

The delivery of a small for gestational age baby impacts families and health care systems alike although a critical challenge is distinguishing those that are born constitutionally small from those with intrauterine undernourishment that are at increased risk for adverse outcomes. We have developed a new approach for measuring umbilical venous blood flow using 3D ultrasound and Doppler technology across all trimesters of pregnancy. In this proposal, we explain how we will determine accuracy, reproducibility, normal reference standards, and circulatory findings in small fetuses, based on 3D umbilical venous blood flow, to improve our ability for detecting and monitoring pregnancies with suspected growth abnormalities from intrauterine undernourishment.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Weinberg, David H
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Baylor College of Medicine
Obstetrics & Gynecology
Schools of Medicine
United States
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