Chronic hypoxia in pregnant mice impairs the placental and fetal vascular response to acute hypercapnia in BOLD-MRI hemodynamic response imaging.

INTRODUCTION: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model). METHODS: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O2;E13.5-17.5) and early-onset hypoxia (12%O2;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO2). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained. RESULTS: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only. CONCLUSIONS: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury.

BOLD-MRI demonstrates acute placental and fetal organ hypoperfusion with fetal brain sparing during hypercapnia.

INTRODUCTION: We evaluated changes in placental and fetal hemodynamics in rodents during acute hypercapnia using BOLD-MRI and Doppler ultrasound. METHODS: Animals were anesthetized with pentobarbital and, in consecutive 4-min periods, breathed: air, 21%O2:5%CO2, and 95%O2:5%CO2. BOLD-MRI: Pregnant ICR mice (n = 6; E17.5) were scanned in a 4.7-T Bruker Biospec spectrometer. Placenta and fetal liver, heart and brain were identified on True-FISP images. Percent change in signal intensity (SI) were analyzed every 30 s from T2*-weighted GE images (TR/TE = 147/10 ms). Doppler: Pregnant Wistar rats (n = 6; E18-20) were anesthetized with pentobarbital and received abdominal Doppler ultrasound. Umbilical artery pulsatility index (PI) and fetal heart rate were assessed at baseline and after two minutes of both hypercapnic challenges. RESULTS: BOLD-MRI: Normoxic-hypercapnia caused immediate marked reduction in SI in placenta (-44% ± 5.5; p < 0.001), fetal liver (-32% ± 6.4; p < 0.001) and fetal heart (-53% ± 9.9; p < 0.001) but only minor changes in fetal brain (-13% ± 3.4; p < 0.01), suggesting fetal brain sparing. Doppler: Normoxic-hypercapnia caused a marked increase in umbilical artery PI (+27.4% ± 7.2; p < 0.001) and a reduction in fetal heart rate (-48 bpm; 95%CI -9.3 to -87.0; p = 0.02), suggesting acute fetal asphyxia. CONCLUSIONS: Brief maternal hypercapnic challenge caused BOLD-MRI changes consistent with acute placental and fetal hypoperfusion with fetal brain sparing. The same challenge caused increased umbilical artery PI and fetal bradycardia on Doppler ultrasound, suggestive for acute fetal asphyxia. BOLD-MRI may be a suitable noninvasive imaging strategy to assess placental and fetal organ hemodynamics.