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Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

Background: 3D chemical shift-encoded (CSE)-MRI techniques enable assessment of ferumoxytol concentration but are unreliable in the presence of motion.Purpose: To evaluate a motion-robust 2D-sequential CSE-MRI for R2* and B0 mapping in ferumoxytol-enhanced MRI of the placenta.Study Type: Prospective.Animal Model: Pregnant rhesus macaques.Field Strength/sequence: 3.0T/CSE-MRI.Assessment: 2D-sequential CSE-MRI was compared with 3D respiratory-gated CSE-MRI in placental imaging of 11 anesthetized animals at multiple timepoints before and after ferumoxytol administration, and in ferumoxytol phantoms (0 μg/mL-440 μg/mL). Motion artifacts of CSE-MRI in 10 pregnant women without ferumoxytol administration were assessed retrospectively by three blinded readers (4-point Likert scale). The repeatability of CSE-MRI in seven pregnant women was also prospectively studied.Statistical Tests: Placental R2* and boundary B0 field measurements (ΔB0) were compared between 2D-sequential and 3D respiratory-gated CSE-MRI using linear regression and Bland-Altman analysis.Results: In phantoms, a slope of 0.94 (r2 = 0.99, concordance correlation coefficient ρ = 0.99), and bias of -4.8 s-1 (limit of agreement [LOA], -41.4 s-1 , +31.8 s-1 ) in R2*, and a slope of 1.07 (r2 = 1.00, ρ = 0.99) and bias of 11.4 Hz (LOA -12.0 Hz, +34.8 Hz) in ΔB0 were obtained in 2D CSE-MRI compared with 3D CSE-MRI for reference R2* ≤390 s-1 . In animals, a slope of 0.92 (r2 = 0.97, ρ = 0.98) and bias of -2.2 s-1 (LOA -55.6 s-1 , +51.3 s-1 ) in R2*, and a slope of 1.05 (r2 = 0.95, ρ = 0.97) and bias of 0.4 Hz (LOA -9.0 Hz, +9.7 Hz) in ΔB0 were obtained. In humans, motion-impaired R2* maps in 3D CSE-MRI (Reader 1: 1.8 ± 0.6, Reader 2: 1.3 ± 0.7, Reader 3: 1.9 ± 0.6), while 2D CSE-MRI was motion-free (Reader 1: 2.9 ± 0.3, Reader 2: 3.0 ± 0, Reader 3: 3.0 ± 0). A mean difference of 0.66 s-1 and coefficient of repeatability of 9.48 s-1 for placental R2* were observed in the repeated 2D CSE-MRI.Data Conclusion: 2D-sequential CSE-MRI provides accurate R2* and B0 measurements in ferumoxytol-enhanced placental MRI of animals in the presence of respiratory motion, and motion-robustness in human placental imaging.Level Of Evidence: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:580-592. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the correspondence between arterial spin labeling (ASL) flow‐sensitive alternating inversion recovery (FAIR) and ferumoxytol DCE MRI for the assessment of placental intervillous perfusion. Methods: Ten pregnant macaques in late second trimester were imaged at 3 T using a 2D ASL FAIR, with and without outer‐volume saturation pulses used to control the bolus width, and a 3D ferumoxytol DCE‐MRI acquisition. The ASL tagged/control pairs were averaged, subtracted, and normalized to create perfusion ratio maps. Contrast arrival time and uptake slope were estimated by fitting the DCE data to a sigmoid function. Macaques (N = 4) received interleukin‐1β to induce inflammation and disrupt perfusion. Results: The FAIR tag modification with outer‐volume saturation reduced the median ASL ratio percentage compared with conventional FAIR (0.64% ± 1.42% versus 0.71% ± 2.00%; P <.05). Extended ferumoxytol arrival times (34 ± 25 seconds) were observed across the placenta. No significant DCE signal change was measured in fetal tissue (−0.6% ± 3.0%; P =.52) or amniotic fluid (1.9% ± 8.8%; P =.59). High ASL ratio was significantly correlated with early arrival time and high uptake slope (P <.05), but ASL signal was not above noise in late‐DCE‐enhancing regions. No significant differences were observed in perfusion measurements between the interleukin‐1β and controls (P >.05). Conclusion: The ASL‐FAIR and ferumoxytol DCE‐MRI methods are feasible to detect early blood delivery to the macaque placenta. Outer volume saturation reduced the high macrovascular ASL signal. Interleukin‐1β exposure did not alter placental intervillous perfusion. An endogenous‐labeling perfusion technique is limited due to extended transit times for flow within the placenta beyond the immediate vicinity of the maternal spiral arteries. [ABSTRACT FROM AUTHOR]

Background: Pregnancy complications are often associated with poor uteroplacental vascular adaptation and standard diagnostics are unable to reliably quantify flow in all uteroplacental vessels and have poor sensitivity early in gestation.Purpose: To investigate the feasibility of using 4D flow MRI to assess total uteroplacental blood flow in pregnant rhesus macaques as a precursor to human studies.Study Type: Retrospective feasibility study.Animal Model: Fifteen healthy, pregnant rhesus macaques ranging from the 1st trimester to 3rd trimester of gestation.Field Strength/sequence: Abdominal 4D flow MRI was performed on a 3.0T scanner with a radially undersampled phase contrast (PC) sequence. Reference ferumoxytol-enhanced angiograms were acquired with a 3D ultrashort echo time sequence with a center-out radial trajectory.Assessment: Repeatability of flow measurements was assessed with scans performed same-day and on consecutive days in the uterine arteries and ovarian veins. In-flow was compared against out-flow in the uterus, umbilical cord, and fetal heart with a conservation of mass analysis. Conspicuity of uteroplacental vessels was qualitatively compared between PC angiograms derived from 4D flow data and ferumoxytol-enhanced angiograms.Statistical Tests: Bland-Altman analysis was used to quantify same-day and consecutive-day repeatability.Results: Same-day flow measurements showed an average difference between scans of 13% in both the uterine arteries and ovarian veins, while consecutive-day measurements showed average differences of 22% and 24%, respectively. Comparisons of in-flow and out-flow showed average differences of 15% in the uterus, 8% in fetal heart, and 15% in the umbilical cord. PC angiograms showed similar depiction of main uteroplacental vessels as high-resolution, ferumoxytol-enhanced angiograms.Data Conclusion: 4D flow MRI could be used in the rhesus macaque for repeatable flow measurements in the uteroplacental and fetal vasculature, setting the stage for future human studies.Level Of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:534-545. [ABSTRACT FROM AUTHOR]