Background: Blood oxygen level dependant functional MRI (BOLD-fMRI) has been used to image changes in uterine perfusion without contrast agent administration during hypoxia in pregnant sheep.¹ We further developed the BOLD-fMRI method by utilizing brief challenges of hypercapnia followed by hypercapnia-hyperoxia for monitoring acute changes in organ perfusion without contrast administration.^2-3 We used this technique to assess uteroplacental and fetal organ perfusion, in order to assess the acute fetal responses to hypercarbic and hyperoxic challenge, and to assess whether these responses are affected by chronic maternal hypoxia, as a model of intrauterine fetal asphyxia.⁴ 

Methods Pregnant female ICR mice (n=6 mice/group) were either kept under normoxic conditions or were exposed to chronic hypoxia (12% FiO₂) on gestational days 10-18 (early hypoxia) or days 13-18 (late hypoxia). Chronic hypoxia was induced using a hypoxic chamber (Coy Laboratory Products). On the 18th day, anesthetized mice (pentobarbital) were scanned in a 4.7-T Bruker Biospec spectrometer. Changes in placental and fetal perfusion were analyzed from T2*-weighted GE images (TR/TE=147/10 ms) acquired during breathing of air (4 min), air-carbon dioxide (5% CO₂) (4 min), and carbogen (95% O₂-5% CO₂) (4 min). Different regions of interest (placenta, and fetal heart, liver and brain) were identified on True-FISP images using IDL software. Percentage change in signal intensity induced by hypercapnia (ΔS_CO2) and hyperoxia (ΔS_O2) was calculated and presented by color maps and time curves. After MRI, fetuses and placentas were taken for histological evaluation. 

Results BOLD-fMRI provided simultaneous assessments of placental and fetal organs (brain, heart, liver) perfusion in pregnant mice. We observed that acute maternal hypercapnia caused reproducible and reversible reductions in perfusion of placenta, fetal liver and heart. Fetal cerebral perfusion was unchanged; suggestive of the described phenomenon of fetal “brain sparing” (Fig 1). The acute hypercapnia challenge using BOLD-fMRI was able to distinguish between chronic intrauterine asphyxia (induced by maternal hypoxia) and normal controls, with lower % change in placental perfusion and less fetal brain sparing (Figs 1, 2). 

 

Fig 1 Representatives coronal FISP images (left); the corresponding BOLD-fMRI (ΔS) maps (middle) and the related time courses of SI change

from the different regions obtained from normoxic (Top), late hypoxic (Middle) and early hypoxic (Bottom) pregnant ICR mice (day 18 of gestation – E18).

Fig. 2 Mean ΔS values of different fetal and maternal organs obtained from normoxic, early hypoxic and late hypoxic pregnant ICR mice E18 (*p<0.001 compare to normoxia).

Conclusions:  The BOLD-fMRI hypercapnic challenge test was able to differentiate between normal and chronically asphyxiated pregnancies.

Further preclinical and clinical investigation is required to assess whether these observations may herald the use of this non-invasive diagnostic tool to determine if the severity of chronic intrauterine fetal asphyxia justifies interventional delivery. 

References: ¹Wedegärtner U, Radiology 238:872,2006;² Barash H, Radiolog243:727,2007; ³Barash H, Hepatology 48:1232, 2008. ⁴ Tomlinson T, Am J Physiol Regul

Integr Comp Physiol 298: R312, 2010.

 

Authors:

Yehuda Ginosar¹, Nathalie Corchia², Uriel Elchalal³, Rinat Abramovitch ²

¹Department of Anesthesiology, ²The Goldyne Savad Institute of Gene Therapy and³Department of Obstetrics and Gynecology; Hadassah Hebrew University Medical Center, Jerusalem, Israel.