A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR

Madeline M Ross, Sara Cherkerzian, Nicole D Mikulis, Daria Turner, Julian Robinson, Terrie E Inder, Lillian G Matthews, Madeline M Ross, Sara Cherkerzian, Nicole D Mikulis, Daria Turner, Julian Robinson, Terrie E Inder, Lillian G Matthews

Abstract

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24-34 weeks' gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women's Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://ichgcp.net/clinical-trials-registry/NCT04394910 , Registered May 20, 2020, initial participant enrollment January 16, 2016.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
CONSORT participant flowchart.
Figure 2
Figure 2
Brain injury risk by study arm on mITT and PP analysis. Risk difference and 95% confidence intervals are shown (Placebo = reference). Lines to the left of 0 favor pomegranate juice, i.e. infants randomized to pomegranate juice demonstrate lower risk of brain injury compared with infants randomized to placebo. Lines that do not cross 0 denote a significant difference in risk, p < 0.05. (a) Modified intention-to-treat (mITT) analysis. (b) PP analysis. (c) PP analysis excluding infants born to mothers positive for metabolites at enrollment. CB cerebellum; DGM deep grey matter; GM cortical grey matter; IVH intraventricular hemorrhage; POM pomegranate; WM white matter.
Figure 3
Figure 3
Representative brain MRIs demonstrating Kidokoro injury scoring. T1-weighted coronal slices from six representative infants exposed in utero to pomegranate juice (top row) or placebo (bottom row). (A–C) No injury detected—normal scores for gyral maturation, PLIC myelination, extra-axial space/IHD (arrows). (D–F) Representative injury categories detected; (D)—2 points for WM focal signal abnormality (arrows); (E)—2 points for focal signal abnormality, 1 point for myelination delay, 1 point for gyral maturation delay (arrow), 1 point for IHD (arrow); (F)—1 point for gyral maturation delay, 2 points for IHD, 2 points for lateral ventricle enlargement (arrow). IHD interhemispheric distance; PLIC posterior limb of the internal capsule; WM white matter.

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